Lecture 23 - Pathophysiology of the kidney

Question 1

What is diabetes insipidus?

Answer 1

Rare disease in which the kidneys produce abnormally large volumes of dilute urine

Question 2

Where is vasopressin (ADH) produced?

Answer 2

Hypothalamus

Question 3

Where is ADH stored?

Answer 3

Posterior pituitary

Question 4

Where does ADH bind?

Answer 4

Vasopressin binds to the vasopressin receptor (V2) on the basolateral membrane of LDT and CD cells

Question 5

What happens when V2 is activated?

Answer 5

When V2 is activated, we have the incorporation of AQP2 channels into the apical membrane = increase H2O flow

Question 6

What are symptoms of DI?

Answer 6

Polyuria
Polydipsia
First year of life - vomiting, fever, slow growth, developmental delay
Severe dehydration
Severe cases - mental deficiency due to dehydration of the brain

Question 7

What is DI?

Answer 7

Diabetes insipidus

Question 8

What is polyuria?

Answer 8

Large volume of urine - hypotonic urine (> 15 L/d)

Question 9

What is polydipsia?

Answer 9

Excessive drinking

Question 10

What are the two types of DI?

Answer 10

Central Diabetes Insipidus (Neurogenic DI) - CDI
Nephrogenic Diabetes Insipidus - NDI

Question 11

What is the cause of CDI?

Answer 11

lack of production of vasopressin (ADH) by the hypothalamus or release from the posterior pituitary gland

Question 12

What brain region is most likely affected in CDI?

Answer 12

Posterior pituitary as hypothalamus is involved with many processes, so if damaged there would be other diseases not just CDI

Question 13

What is the cause of NDI?

Answer 13

Problem at the level of the kidney
Congenital X-Linked NDI - mutated V2 receptor
– 90% of NDI patients
– Normally males
Autosomal NDI - mutated AQP2 channel
– 10% of NDI patients
– Normal V2 function

Question 14

What does mutations of V2 receptor and AQP2 result in? (5)

Answer 14

• non-functional AQP2 channels and V2 receptors
• ineffective biosynthesis of protein (AQP2 or V2)
• simple binding impairment of V2 receptors
• intracellular trafficking problems (AQP2 or V2)
• accelerated degradation of AQP2 channel or V2 receptor to the proteasome or lysosome

Question 15

Which of the following statements is TRUE?
A. Vasopressin is produced in the supraoptic and paraventricular nuclei of the posterior pituitary gland.
B. Central diabetes insipidus is a problem with vasopressin production, storage and release from the hypothalamus
C. Nephrogenic diabetes insipidus (NDI) is a problem at the level of the late distal tubule and collecting duct.
D. Individuals with NDI exhibit reduced urine production.

Answer 15

C. Nephrogenic diabetes insipidus (NDI) is a problem at the level of the late distal tubule and collecting duct.

Question 16

What is Bartter’s Syndrome?

Answer 16

• autosomal recessive disorder
  – 1:50,000 to 1:100,000 births
• salt-wasting (NaCl loss in urine)
• hypereninism and hyperaldosteronism
• metabolic alkalosis
• hypokalaemia (low blood K+)

Question 17

What proteins are effected in Bartter’s syndrome and where are they located?

Answer 17

In Bartter’s syndrome there is a problem with the transport proteins of the epithelial cells of the Thick Ascending Limb

Question 18

What are the three types of Bartter’s syndrome and what transport protein is affected in each?

Answer 18

Bartter’s Syndrome Type 1
– apical Na+-K+-2Cl- cotransporter (NKCC2)
Bartter’s Syndrome Type 2
– apical K+ channel (ROMK1)
Bartter’s Syndrome Type 3
– basolateral Cl- channel (CLCNKB)

Question 19

What is the normal function of the TAL?

Answer 19

Normal function of the TAL is to reabsorb Na+, K+ and Cl

Question 20

What syndrome affects NKCC2 in the TAL?

Answer 20

Bartter’s Syndrome Type 1

Question 21

What syndrome affects ROMK1 in the TAL?

Answer 21

Bartter’s Syndrome Type 2

Question 22

What syndrome affects CLCNKB in the TAL?

Answer 22

Bartter’s Syndrome Type 3

Question 23

What is CLCNKB?

Answer 23

Volatage gate chloride channel predominantly found in kidneys - TAL

Question 24

What happens when there are mutations of NKCC2, ROMK1 and CLCNKB? (5)

Answer 24

• non-functional channels or co-transporters
• ineffective biosynthesis of protein
• simple binding impairment of NKCC2
• intracellular trafficking problems
• accelerated degradation of the channels or co-transporters

Question 25

Which of the following statements is TRUE?
A. Bartter’s Syndrome Type 3 (BS3) is a problem with the Distal tubule.
B. BS patients exhibit hyporeninism and
hypoaldosteronism.
C. BS1 patients have a mutations of the Na-K-2Cl cotransporter.
D. BS3 patients exhibit hyperkalaemia.

Answer 25

C. BS1 patients have a mutations of the Na-K-2Cl cotransporter.

A - TAL not DT
B - Hypereninism not hyporeninism
D - Hypokalaemia not hyperkalaemia

Question 26

What areas of the kidney are affected in Liddle’s syndrome?

Answer 26

Late Distal Tubule and Collecting Duct

Question 27

What are the symptoms of Liddle’s syndrome?

Answer 27

Hypertension due to increased Na+ reabsorption
Hypokalaemic metabolic alkalosis
Pseudoaldosteronism
Suppressed levels of aldosterone and renin

Question 28

What happens to the principal cells in Liddle’s syndrome?

Answer 28

Increased Na+ reabsorption leads to increased negative (-) luminal voltage. This leads to increased K+ secretion.
Hence, hypokalaemia (low blood K+)

Question 29

What happens to the intercalated cells in Liddle’s syndrome?

Answer 29

The increased luminal negative voltage (created by the principal cells) causes H+ secretion and HCO3- recycling by the intercalated cells. Hence, metabolic alkalosis - increase H+ loss and gain of HCO3

Question 30

Why is there increased Na+ reabsorption by the CD in patients with Liddleʼs Syndrome?

Answer 30

Mutations in the COOH terminus of ENaC causes the channel to remain at the membrane indefinitely. Leading to hyperabsorption of Na+ with increased secretion of K+

Question 31

What does hyperabsorption of Na+ cause?

Answer 31

Hypertension

Question 32

Which of the following statements is FALSE?
A. Liddle’s Syndrome patients have hypokalaemia.
B. The number of ENaC channels at the apical membrane are increased in patients who have Liddle’s Syndrome.
C. In Liddle’s Syndrome, patients have hyperaldosteronism.
D. The R556X mutation of ENaC results in too many ENaC channels at the apical membrane of cells of the Collecting Duct.

Answer 32

C. In Liddle’s Syndrome, patients have hyperaldosteronism. - In Liddle’s syndrome there is pseudoaldosteronism

Question 33

What does molecular diseases of the renal tubule lead to?

Answer 33

Abnormal reabsorption or secretion