Renal diseases

Question 1

What is Liddles syndrome

Answer 1

Autosomal dominant inheritance - Na and fluid retention - hypertension and hypokalemia
Low renin and aldosterone levels

Question 2

Where is the problem found for Liddles syndrome

Answer 2

Principal cells of the collecting duct - ENaC - Liddles mutation in the carboxy terminus of beta and gamma subunits

Question 3

How does the mutation in ENaC lead to hypertension

Answer 3

Deletion of proline rich motifs used for intracellular signalling - This is necessary for endocytosis from the principal cell - Can’t reuptake ENaC at normal rate so there is excess Na and water reuptake

Question 4

How does Liddles lead to hypokalemia

Answer 4

High Na reuptake means there is more K secretion via ROMK

Question 5

How does Liddles lead to a transepithelial potential and therefore a metabolic alkalosis

Answer 5

In the alpha intercalated cells - Absorbing Na leaves behind a negative charge - this drives H secretion - Loss of H causes a metabolic alkalosis

Question 6

What happens to levels of aldosterone and renin in response to increased BP

Answer 6

They drop - low aldosterone causes loss of ENaC from apical membrane of the principal cells - so reduced Na reabsorption so reduced fluid retention

Question 7

How do Liddles sufferers renin and aldosterone behave

Answer 7

In increased BP low aldosterone and renin still occur but they are unable to remove ENaC from the apical membrane - so there is no reduction in reabsorption

Question 8

What is used to treat liddles syndrome

Answer 8

Amiloride - blocks the function of ENaC

Question 9

What is diabetes insipidus

Answer 9

AQP2 and AVP mutations

Question 10

What is the normal action of vasopressin

Answer 10

Produced in the hypothalamus, released from the posterior pituitary gland - acts on V2 receptors on the basolateral membrane of the principal cells - causes adenylate cyclase action - cAMP - PKA phosphorylates aquaporins in vesicles which leads to their transport to the apical membrane - water reabsorption

Question 11

What is type 1 diabetes insipidus

Answer 11

Primary polydipsia - suppressed AVP production - caused by excessive water intake

Question 12

What is type 2 diabetes insipidus

Answer 12

Gestational - Decreased AVP levels - metabolized by placental enzymes - relieved after childbirth

Question 13

What is type 3 diabetes insipidus

Answer 13

Central - Impaired AVP production - can be acquired or congenital

Question 14

What is type 4 diabetes insipidus

Answer 14

Nephrogenic - impaired effect of AVP - can be acquired or congenital

Question 15

What are causes of central diabetes insipidus which is acquired

Answer 15

Infection, trauma, surgery - damage to pituitary gland

Question 16

What are the causes of central diabetes insipidus which is congenital

Answer 16

Neurohypophyseal diabetes insipidus - 67 mutations in AVP gene - many mutations in sites important for AVP transport of AVP to the posterior pituitary gland

Question 17

What are the causes of nephrogenic diabetes insipidus which is acquired

Answer 17

More common - Lithium for bipolar treatment

Some antibiotics, antifungals, hypokalemia, hypercalciuria, acute and chronic renal failure

Question 18

What are the causes of nephrogenic diabetes insipidus which is congenital

Answer 18

Mutations in AVPR2 or AQP2 genes
AVPR2 genes are x linked
AQP2 gene impacts on trafficking(dominant), or function of protein (recessive)
Symptoms appear in infants

Question 19

What are treatments of central diabetes insipidus

Answer 19

Desmopressin - increases urine osmolality by stimulating V2 receptors

Question 20

How are nephrogenic causes treated

Answer 20

Difficult - possibly:
Modulator drugs - protein misfolded but still functioning 
Pharmacological chaperones 
Cell permeable receptor agonists
cGMP and cAMP antagonists
Prostaglandins
Heat shock protein 90