Renal Tubular Function 2

Question 1

What are the functional components of the Loop of Henle?

Answer 1

1 - Descending limb.

2 - Thick ascending limb (thin ascending limb not relevant for you).

Question 2

What is the overall function of the thick ascending limb?

Answer 2

To create a hyperosmolar interstitial space in the medulla to drive water loss from the descending limb and collecting duct, ultimately increasing water reabsorption.

Question 3

How does the water permeability of the descending limb differ from that of the ascending limb?

Answer 3

The (thick) ascending limb is impermeable to water, whereas the descending limb is permeable to water.

Question 4

How does the thick ascending limb create a hyperosmolar interstitial space in the medulla?

Answer 4

• By using a Na+/K+/2Cl- cotransporter, known as NKCC2 to pump these ions out of the filtrate and into the interstitial space.
• K+ recycling through the apical membrane is necessary to ensure that the transporter can continue transporting large quantities of Na+ and Cl-. This occurs through apical K+ leak channels that allow passage of K+ back into the filtrate.
• On the basolateral membrane, sodium/potassium pumps transport 3Na+ into the interstitial space and 2 K+ into the epithelial cell.
• Basolateral K+ and Cl- leak channels are also present. The K+ leak channel increases the action of the Na+/K+ pump.

Question 5

What is furosemide?

Describe its mechanism of action.

Answer 5

• A loop diuretic.

- It blocks the NKCC2 pump, allowing up to 20% of the filtrate Na+ to be excreted, causing natriuresis and diuresis.

Question 6

Define loop diuretic.

Answer 6

A diuretic that acts in the ascending limb.

Question 7

List 2 clinical uses of furosemide.

Answer 7

1 - Used to treat cardiac failure.

2 - Used to treat renal failure.

Question 8

List 7 side effects of furosemide use.

Answer 8

1 - Hypokalaemia.

2 - Hyponatraemia.

3 - Cardiac arrhythmias (due to K+ loss, particularly when administered with digoxin).

4 - Hypovolaemia.

5 - Mild metabolic alkalosis.

6 - Loss of Mg2+.

7 - Loss of Ca2+.

Question 9

Why might furosemide cause mild metabolic alkalosis?

Answer 9

• Due to increased action of the Na+/H+ exchanger in the distal tubule.
• This occurs as there is more Na+ in the filtrate that can pass through the Na+/H+ exchanger, resulting in more H+ being excreted.

Question 10

What concentration gradient can the thick ascending limb maintain?

Answer 10

200mOsm kg^-1.

Question 11

What is the osmolality of filtrate entering the thick ascending limb?

Answer 11

~285mOsm kg^-1.

Question 12

Describe the process of Na+ absorption in the distal tubule.

Answer 12

• A Na+/Cl- cotransporter on the apical surface of epithelial cells transports both Na+ and Cl- into the epithelial cell.
• Na/K+ pumps on the basolateral surface secrete Na+ into the interstitial space and maintain the gradient of Na+ across the cell.
• K+/Cl- cotransporters on the basolateral surface secrete both K+ and Cl- into the interstitial space.

Question 13

What are thiazides / thiazide-like drugs?

Describe their mechanism of action.

With which drug is it normally administered?

Answer 13

• Diuretics.
• They block the Na+/Cl- cotransporters on the apical surface of epithelial cells in the distal tubule, inhibiting Na+ and Cl- reabsorption.
• Usually administered with furosemide.

Question 14

List 3 side effects of thiazides / thiazide-like drugs.

Answer 14

1 - Increased uric acid.

2 - Hyperglycaemia.

3 - Hyponatraemia.

Question 15

Via which channels does water pass through the apical and basolateral surfaces of the epithelial cells in the collecting duct?

What is the effect of ADH on these channels?

Answer 15

• AQP2 at the apical membrane.
• AQP3 at the basolateral membrane.
• ADH increases the number of AQP2 channels only.

Question 16

What is the effect of aldosterone at the collecting duct?

How does this influence the movement of water in the collecting duct?

Answer 16

• Aldosterone stimulates the synthesis of Na+ leak channels on the apical membrane and Na+/K+ pumps on the basolateral membrane.
• Na+ is pumped out of the basolateral membrane, and K+ is pumped in. This drives Na+ entry and K+ exit at the apical membrane.
• Water movement is driven by Na+ entry into the cells.

Question 17

What is spironolactone?

Describe its mechanism of action.

Answer 17

• A diuretic.
• Blocks the effect of aldosterone, decreasing synthesis of basolateral Na+/K+ pumps, thereby reducing water entry into the epithelial cell due to decreased Na+ movement into the cell.

Question 18

What is amiloride?

Describe its mechanism of action.

Answer 18

• A diuretic.

- Blocks the apical ENaC Na+ channel at the collecting duct, reducing water entry into the epithelial cell.

Question 19

Why are spironolactone and amiloride ideal diuretics for patients with heart failure?

Answer 19

Because they are K+ sparing diuretics (they do not cause K+ loss).

Question 20

List 3 side effects of spironolactone.

Answer 20

1 - Gynaecomastia.

2 - Menstrual disorders.

3 - Testicular atrophy.

Question 21

Why might amiloride and spironolactone cause hyperkalaemia?

Answer 21

• If less sodium is able to enter the cell on the apical membrane, then less K+ will be able to enter the cell on the basolateral membrane via the Na+/K+ pump.
• More K+ remains in the interstitial space and is reabsorbed into the blood.

Question 22

What is eplerenone?

Describe its mechanism of action.

Answer 22

• A newer, more specific mineralocorticoid inhibitor than spironolactone.
• Mechanism is presumably the same as spironolactone’s.

Question 23

List the components of the collecting duct.

Answer 23

1 - Cortical collecting duct.

2 - Medullary collecting duct.

Question 24

How does the urea permeability of the cortical collecting duct differ from that of the medullary collecting duct?

Answer 24

The cortical collecting duct is impermeable to urea, whereas the medullary collecting duct is permeable to urea.

Question 25

What determines urea permeability in the medullary collecting duct?

Which hormone controls this?

Answer 25

• The presence of urea transporter A1.

- ADH increases the expression of urea transporter A1.

Question 26

How, and between which components of the nephron, is a urea countercurrent set up?

Answer 26

• Urea is able to diffuse out of the medullary collecting duct into the interstitial space.
• This contributes to the high osmolality in the medulla.
• This drives water movement in the descending limb of the loop of henle, aiding water reabsorption in the medulla.