Lecture 23 - Pathophysiology of the kidney Flashcards
What is diabetes insipidus?
Rare disease in which the kidneys produce abnormally large volumes of dilute urine
Where is vasopressin (ADH) produced?
Hypothalamus
Where is ADH stored?
Posterior pituitary
Where does ADH bind?
Vasopressin binds to the vasopressin receptor (V2) on the basolateral membrane of LDT and CD cells
What happens when V2 is activated?
When V2 is activated, we have the incorporation of AQP2 channels into the apical membrane = increase H2O flow
What are symptoms of DI?
Polyuria
Polydipsia
First year of life - vomiting, fever, slow growth, developmental delay
Severe dehydration
Severe cases - mental deficiency due to dehydration of the brain
What is DI?
Diabetes insipidus
What is polyuria?
Large volume of urine - hypotonic urine (> 15 L/d)
What is polydipsia?
Excessive drinking
What are the two types of DI?
Central Diabetes Insipidus (Neurogenic DI) - CDI
Nephrogenic Diabetes Insipidus - NDI
What is the cause of CDI?
lack of production of vasopressin (ADH) by the hypothalamus or release from the posterior pituitary gland
What brain region is most likely affected in CDI?
Posterior pituitary as hypothalamus is involved with many processes, so if damaged there would be other diseases not just CDI
What is the cause of NDI?
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
What does mutations of V2 receptor and AQP2 result in? (5)
- 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
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.
C. Nephrogenic diabetes insipidus (NDI) is a problem at the level of the late distal tubule and collecting duct.
What is Bartter’s Syndrome?
- 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+)
What proteins are effected in Bartter’s syndrome and where are they located?
In Bartter’s syndrome there is a problem with the transport proteins of the epithelial cells of the Thick Ascending Limb
What are the three types of Bartter’s syndrome and what transport protein is affected in each?
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)
What is the normal function of the TAL?
Normal function of the TAL is to reabsorb Na+, K+ and Cl
What syndrome affects NKCC2 in the TAL?
Bartter’s Syndrome Type 1
What syndrome affects ROMK1 in the TAL?
Bartter’s Syndrome Type 2
What syndrome affects CLCNKB in the TAL?
Bartter’s Syndrome Type 3
What is CLCNKB?
Volatage gate chloride channel predominantly found in kidneys - TAL
What happens when there are mutations of NKCC2, ROMK1 and CLCNKB? (5)
- 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
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.
C. BS1 patients have a mutations of the Na-K-2Cl cotransporter.
A - TAL not DT
B - Hypereninism not hyporeninism
D - Hypokalaemia not hyperkalaemia
What areas of the kidney are affected in Liddle’s syndrome?
Late Distal Tubule and Collecting Duct
What are the symptoms of Liddle’s syndrome?
Hypertension due to increased Na+ reabsorption
Hypokalaemic metabolic alkalosis
Pseudoaldosteronism
Suppressed levels of aldosterone and renin
What happens to the principal cells in Liddle’s syndrome?
Increased Na+ reabsorption leads to increased negative (-) luminal voltage. This leads to increased K+ secretion.
Hence, hypokalaemia (low blood K+)
What happens to the intercalated cells in Liddle’s syndrome?
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
Why is there increased Na+ reabsorption by the CD in patients with Liddleʼs Syndrome?
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+
What does hyperabsorption of Na+ cause?
Hypertension
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.
C. In Liddle’s Syndrome, patients have hyperaldosteronism. - In Liddle’s syndrome there is pseudoaldosteronism
What does molecular diseases of the renal tubule lead to?
Abnormal reabsorption or secretion
