Regulation of the effective circulating volume

Question 1

What are the water permeability characteristics of the different segments of the nephron

Answer 1

• Maintaining the water balance (fluid volume) is highly regulated by the kidneys as it produces concentrated or diluted urine based on the status of the body

Question 2

What is the importance of maintaining the fluid levels in the body?

Answer 2

1. Prevents dehydration or overhydration
2. Prevents cellular shrinking (in hyperosmolarity status) or swelling (in hypoosmolar status)
3. Prevents ion imbalances (hyper and hypo)

Question 3

Describe the permeability of water, sodium chloride, and urea in the proximal tubule

Answer 3

• It has a high amount of active NaCl transporters

1) Water: High permeability (via aquaporin 1)

2) NaCl: Moderate permeability

3) Urea: Moderate permeability

• Urea is reabsorbed at the distal portion of the PCT passively as sodium and water are absorbed its concentration in the filtrate increases creating a diffusion gradient that promotes its reabsorption

Question 4

Describe the permeability of water, sodium chloride, and urea in the thin descending limb

Answer 4

• It has minimal levels of active NaCl transporters

1) Water: Highly reabsorbed (via aquaporin 1)

2) NaCl: Moderately reabsorbed

3) Urea: Moderately reabsorbed

• After this segment water permeability ceases as the ascending limbs are impermeable to water

Question 5

Describe the permeability of water, sodium chloride, and urea in the thin ascending limb

Answer 5

• It does not have active NaCl transporters

1) Water: Minimally permeable (impermeable to water)

2) NaCl: moderately permeable

3) Urea: Moderately permeable

Question 6

Describe the permeability of water, sodium chloride, and urea in the thick ascending limb

Answer 6

• High levels of active NaCl transporter via the Na/K/2Cl cotransporter

1) Water: Impermeable

2) NaCl: Permeable

3) Urea: Impermeable

• Because it is impermeable to water but permeable to NaCl, especially at the segment between the thin ascending and the tick ascending where water reabsorption is zer the medullary interstitium fluid becomes hyperosmolar while the tubular fluid becomes hypoosmolar

Question 7

Describe the permeability of water, sodium chloride, and urea in the distal tubule and the cortical collecting tubule

Answer 7

• Moderate active NaCl transporters

1) Water: Depends on ADH

2) NaCl: Impermeable

3) Urea: Impermeable

Question 8

Describe the permeability of water, sodium chloride, and urea in the inner medullary collecting duct

Answer 8

• Moderate active NaCl transporter

1) Water: ADH dependant

2) NaCl: Impermeable

3) Urea: Depends on ADH

Question 9

ADH increases the permeability of which substances?

Answer 9

Water and urea

• Urea reabsorption is increased by ADH at the inner medullary collecting duct only (none of the other portions of the nephron)

Question 10

In which segments of the nephron is the permeability of water increased due to ADH?

Answer 10

1) Distal tubule

2) Cortical collecting tubule

3) Inner medullary collecting duct

Question 11

Why is water not absorbed from the thin ascending segment and forwards?

Answer 11

Due to the absence of aquaporins

Question 12

What happens to the mechanism of NaCl reabsorption after the thin ascending limb?

Answer 12

It switches from passive to active as the tubular fluid becomes hypoosmolar which eliminates the driving force for the passive solute diffusion

Question 13

What is the corticopapillary osmotic gradient?

Answer 13

• It is the progressive increase in osmolarity from the renal cortex (~300 mOsm/L) to the renal papilla (~1200 mOsm/L). This gradient is essential for the concentration of urine as the loop of Henle and the juxtamedullary nephrons located near the medulla rely on this gradient to concentrate the urine
• Urine made in our body in normal conditions is diluted since the distal segments of the nephron are impermeable to water, whereas, in crisis/dehydration, our body releases ADH to cause water reabsorption

Question 14

How does the kidney generate a hyperosmolarity gradient in the medulla?

Answer 14

1) Countercurrent multiplication system in the loop of Henle which depends on the NaCl deposition to the medullary interstitium (the descending limb is permeable to water “this will make the solution more hyperosmolar”, but then the ascending limb will reabsorb the solute only but since water is reabsorbed earlier there will be a stronger drive for the solute reabsorption)

2) Urea recycling: a function of the inner medullary collecting ducts that is permeable to urea and thus will enhance the osmotic gradient producing a concentrated urine

Question 15

The ability to reabsorb water from the filtrate into the bloodstream depends on what?

Answer 15

ADH

Question 16

What are the solutes that contributed to the corticopapillary osmotic gradient

Answer 16

1) Sodium

2) Chloride

3) Urea

Question 17

Elaborate on the countercurrent multiplication system

Answer 17

• This process occurs in the loop of Henle
• The descending limb of the loop is permeable to water but not solutes
• This will concentrate the filtrate
• At the thick ascending loop of Henle Na/K/2Clare pumped out actively, but this segment is impermeable to water diluting the filtrate and concentrating the interstitial fluid of the medulla which is essential for the water reabsorption at the collecting ducts
• This process is called multiplication as the osmolarity in the medulla increases progressively as the filtrate moves through the nephron amplifying the concentration gradient

Question 18

Describe the urea recycling mechanism

Answer 18

• By the time the tubular fluid reaches the medullary collecting tubule the fluid is rich with urea as it is only reabsorbed at the PCT, Thic descending segment, and the thin ascending, only under the influence of ADH urea is reabsorbed at the inner medullary collecting ducts, this will make the medullary interstitium more hyperosmolar and thus more water will get reabsorbed at the medulla, helping with the dehydration crisis

Question 19

Why is the medullary interstitium hyperosmolar and not the cortical region or even the regions from the thin ascending limb?

Answer 19

Because the reabsorption of water under the influence of ADH is higher in the cortical area (DCT and cortical tubules)

Question 20

Summarize the factors that contribute the the hyperosmotic renal medullary interstitium

Answer 20

1) Active transport of Na ions and co-transport of Potassium, chloride, and other ions from the thick ascending limb of the loop of Henle into the medullary interstitium

2) Active transport of ions from the collecting ducts into the interstitium

3) Facilitated diffusion of urea from the inner medullary collecting ducts into the interstitium

4) Diffusion of small amounts of water from the medullary tubules into the interstitium

Question 21

Again how is the countercurrent forming the medullary hyperosmolar interstitium? exact mechanism

Answer 21

1) Initial condition: The loop of Henle is filled with fluid with 300 mOsm/L (the same conc that left the PCT)

2) Active ion pumping in the ascending limb:

• The thick ascending limb actively pumps out sodium and chloride into the surrounding interstitial fluid while the water is unable to follow due to the absence of aquaporins forming a concentrated interstitial fluid (400) and the tubular fluid will become (200 mOsm/L)

3) Osmotic equilibrium in the descending limb:

• Water will move from the descending limb due to osmosis into the interstitial fluid, making the tubular fluid in the descending limb more concentrated (400 mOsm/L), this movement of water persists until equilibrium is reached between the interstitium and the tubular fluid and till the tubular fluid reaches 400 mOsm/L

4) Fluid movement from the PCT

• New filtrate reaches the descending limb from the PCT pushing the concentrated fluid toward the ascending limb

5) More ions are getting pumped

• The ascending limb continues to actively pump ions into the interstitium increasing the osmolarity in the deeper regions (deep regions that are between the ascending and descending limbs)

6) Water moves out to balance the osmolarity

• The interstitium becomes more concentrated, and the water moves out of the descending limb to establish an osmotic equilibrium

7) Maximal concentration in the medulla

• This cycle repeats leading to a progressively increasing osmolarity gradient (up to 1200 mOsm/L in the deepest part of the medulla)

Question 22

What are the net effects of the countercurrent multiplier mechanism?

Answer 22

1. More solute than water is added to the renal medulla (solutes are trapped in the renal medulla)
2. Fluid in the ascending limb is diluted
3. Horizontal gradient of solute concentration is established by the active pumping of NaCl and the concurrent flow of fluid

Question 23

What are the main factors needed to maintain the concurrent multiplier?

Answer 23

1) Active Na/Cl transporter in the thick ascending part

2) Continuous fluid flow into the PCT

3) U-shaped structure of the loop of Henle

-The deepest part of the loop (inner medulla) reaches the highest osmolarity (1200-1400 mOsm/L) because it continuously receives concentrated fluid from the descending limb while the ascending limb keeps on pumping solutes out

Question 24

What determines the capacity of the counter-current multiplication?

Answer 24

1. The size of the corticopapillary gradient depends on the size of the loop of Henle

• FYI in desert rodents the osmolarity can reach to up to 3000 mOsm/L

Question 25

Describe the renal transport of urea

Answer 25

- Urea is the end-product of protein metabolism, the body doesn't reabsorb it but rather it recirculates it for a while which contributes to the hyperosmolarity in the medulla and then it gets rid of it 1) Urea enters the nephron at the glomerulus with a concentration of 4.5 (100% of it is present at the filtrate) 2) As the filtrate moves through the PCT and loop of Henle half of the urea is reabsorbed, but water is reabsorbed with it 3) By the time urine reaches the outer medulla 50% of urea is present at the tubule (the number doesn't decrease much as water is reabsorbed with it and thus making the urea left in the tubular fluid/filtrate more concentrated) 4) In the inner medulla urea is transported across the membrane via the urea transporter (UT-A1, UTA-2, UTA-3) - Urea contributed to 40-50% of the osmolarity - Urea is passively reabsorbed - Urea recirculates through the tubular system several times before being excreted

Question 26

What is the specific function of each urea transporter?

Answer 26

1) UT-A1 & UTA3: They transport urea from the collecting duct back into the interstitial space, ADH activates them and they reabsorb urea from the collecting ducts 2) UT-A2: They are for the urea to be secreted at the thin descending segment - A significant portion of urea is reabsorbed into the interstitial fluid of the inner medulla and then recycled back into the loop of Henle. - Only 20% of the initial urea is ultimately excreted in the urine, showing how much is retained to maintain osmolarity.

Question 27

How does the vasa recta preserve the hyperosmolarity of the renal medulla

Answer 27

- The vasa recta serves as a countercurrent exchanger minimizing the washout of solutes - The vasa recta blood flow is low (only 1/2% of the total renal blood flow), the sluggish blood flow and the U-shape of the vasa recta minimize the loss of solutes from the medullary interstitium - Vasodilators can increase the medullary blood flow and washout the solutes, which would reduce the urine concentrating ability of the nephrons - As the blood enters the descending limb of the vasa recta it has an osmolarity of 300 similar to the plasma and as it moves deeper into the medulla the solute diffuses into the blood and the water moves out - At the ascending limb as the blood moves, the blood moves back towards the cortex it encounters lower osmolarity and thus the solutes diffuse out of the blood and back to the medullary interstitium, and the water moves into the vasa recta diluting the blood making the blood that leaves the vasa recta slightly more hyperosmolar ensuring that the solutes are retained in the medulla

Question 28

How do we form diluted urine?

Answer 28

- Continuous electrolyte reabsorption - Decreased water permeability - Decreased ADH release and reduced water permeability in the distal and collecting tubules

Question 29

What is the obligatory urine volume?

Answer 29

The minimum amount of urine we need to get rid of the minimum amount of solute which is 0.5L/day to get rid of 600 mSom of solutes, this is to maintain an electrolyte balance - We found out that 500ml of urine is needed by 600 (the minimum amount of solvent that must be excreted)/1200 the maximum osmolarity in the body = 500 ml

Question 30

How is ADH triggered and what are its effects?

Answer 30

1) Increased extracellular osmolarity, which makes the osmoreceptors shrink and thus they will fire at a higher rate and generate more AP 2) Increased ADH secretion by the posterior pituitary 3) Increased plasma ADH 4) Increased water permeability in the distal tubules and the collecting ducts 5) Increased water reabsorption 6) Decreased water excretion (which would inhibit the release of ADH)

Question 31

What are the various effects of ADH?

Answer 31

1) Increases the water permeability of the principal cells of the late DCT and the Collecting ducts 2) It increases the activity of the Na-K-2Cl transporters in the thick ascending limb 3) It increases the recycling of urea

Question 32

Where are the osmoreceptors located?

Answer 32

They are special nerve cells that are located in the anterior hypothalamus

Question 33

What is the AV3V?

Answer 33

It is a second neuronal area that is important in controlling the osmolarity and ADH secretion, it is located at the anteroventral region of the third ventricle (AV3V region), and stimulation of this region by angiotensin-2 can increase the ADH secretion, thirst, and sodium appetite

Question 34

How does ADH work?

Answer 34

1. ADH will bind to its receptor (V2 receptors) in the DCT and the collecting tubules 2. The binding of ADH to Ve receptors triggers the Gs protein-mediated activation of adenylate cyclase 3. The Gs protein-mediated activation increases cAMP which will activate protein Kinase A (PKA) 4. PKA phosphorylates aquaporins-2, causing them to move to the apical membrane and fuse with it 5. As a result AQP-2 water channels are inserted into the membrane which will dramatically increase the permeability of water

Question 35

What are the factors that decreases ADH secretion?

Answer 35

1) Decreased osmolarity 2) Increased blood volume (cardiopulmonary reflexes) 3) Increased blood pressure (arterial baroreceptor) 4) Alcohol 5) Haloperidol (antipsychotics, etc)

Question 36

What are the factors that increase the secretion of ADH?

Answer 36

1) Increased osmolarity 2) Decreased blood volume 3) Decreased blood pressure 4) Morphine 5) Nicotine

Question 37

What are the different disorders of the urinary concentrating ability?

Answer 37

1) Inappropriate secretion of ADH 2) Impairment of the counter-current mechanism 3) Inability of the distal tubule, collecting tubule, and collecting ducts to respond to ADH (nephrogenic diabetes insipidus)

Question 38

What is central diabetes insipidus?

Answer 38

- Failure to produce ADH due to (head injuries, infections, congenital - This will result in the inability to reabsorb water at the distal tubular segments - Large volume of diluted urine will be formed - Desmopressin (a synthetic analog of ADH) can rapidly restore the urine output

Question 39

What is meant by the nephrogenic diabetes insipidus?

Answer 39

- An abnormality that resides in the kidney - The renal tubular segments do not respond to ADH - The counter-current mechanism fails and the failure of the tubule segments to respond to ADH - Large volume of diluted urine is formed - To restore the underlying renal disorder must be corrected

Question 40

How to differentiate between nephrogenic, central, and psychogenic?

Answer 40

First, do a water deprivation test (remember one of the most common causes of polyuria is psychogenic polydipsia – you drink a lot of water so your urine output is high). If the patient still has a high urine output even after the deprivation that means its DI. To differentiate between central and nephrogenic, give desmopressin (works like ADH or vasopressin), if the patient gets better that means the problem is due to the release of ADH (central), but if there is no improvement then the body is making ADH it’s just not responding to it properly (nephrogenic)

Question 41

What is meant by free water clearance?

Answer 41

It is the rate at which the kidneys excrete solute-free water

Question 42

How to calculate the free water clearance?

Answer 42

- CH2O represents the rate at which the solute-free water is excreted by the kidneys - Measuring it provides us with a method for assessing the ability of the kidneys to dilute or concentrate urine - It is calculated as the difference between the water excretion and osmolar clearance CH2O = (Urine flow rate (ml/min) - urine osmolarity) * (urine flow rate/plasma osmolarity) or alternatively CH2O = urine flow rate (ml/min) - clearance of osmoles (ml/min)

Question 43

How to interpret the free water clearance data?

Answer 43

1. CH2O = Zero (urine is isosmotic) 2. CH2O = Positive value (urine osmolarity is less than the plasma osmolarity "indicates that water is being removed in excess solutes") 3. CH2O = Negative value (urine osmolarity is greater than the plasma osmolarity "indicates water conservation")