Bartter diseases Flashcards
bartters syndrome symptoms
-polyuria
-hypokalaemia
- metabolic alkalosis
- hypercalciuria -> nephrocalcinosis (calcium deposits forming in the nephron structures
- increased prostaglandin E2 excretion
- hypertrophy of the JGA
- aldosteronism - high aldosterone
- hyperreninaemia - high renin
thick ascending limb main function
is sodium and chloride transport
barter syndrome thick ascending limb
decreased sodium and chloride transport
- leads to impaired ability to concentrate urine
- increased urine volume - decreased blood volume0 detected by juxtaglomerular apparatus
- We get the production of renin
- renin causes angiotensinogen to be converted to Angiotensin one - We then get the conversion to Angiotensin 2 by the ACE enzyme
- and that will eventually lead to aldosterone secretion from the adrenal cortex.
- aldosterone increases the amount of potassium we excrete
- It also increases amount of sodium we reabsorb,
but also because of the potassium excretion We also get more proton excretion.
- that’s one of the reasons with barters why we get hypokalemia and also metabolic
alkalosis.
why altered magnesium and calcium reabsorption
Normally we can get some movement of magnesium and calcium through para cellular transport in the thick ascending limb of the loop of henle, but that may also be disrupted in this system.
- So that may also lead to some of the signs and symptoms where calcium has been changed as well.
what is Bartter syndrome
- inherited group of autosomal recessive disorders (types. 1 - 4)
- incidence approx 1:100,000
- no gender/ racial preference
type 1 and.2 Bartter syndrome
- neonatal Bartter’s appears 24-30 weeks gestation: polyhydramnios
- 4-6 weeks polyuria and polydipsia
- renal function preserved
type 3 Bartter syndrome
classic Bartters evident by 2 years old
- hypokalaemia/ hypochloraemia, metabolic alkalosis
- increase renin and aldosterone and reduced responsiveness to angiotensin 2
3 main ion transport mechanisms from the thick ascending limb of Henle’s loop
- NKCC2 (BSC1) - apical
- CLC-Kb-cl- channel - basolateral membrane
- ROM K channel - apical
Bartter syndrome will disrupt these transporters in some way
sodium transport in TALH
sodium-potassium ATPase creates the sodium gradient for sodium to stay low in the cell - so sodium always wants to come in
- NKCC2 is activated, Sodium comes in ,sodium than can leave by the sodium-potassium atpase and be reabsorbed
- potassium can come in- it can either be reabsorbed through this channel here or it can be recycled here
and chloride can exit the cell through these specific chloride channels, okay.
mutated proteins in the disease - NKCC2
NKCC2
- expected = similar with loop diuretic
- confirmed when NKCC2 ‘cloned’
- knockout studies
ROMK
- identified by expression cloning
ClC-Kb
- kidney specific ClC channel
- cloned by homology with other ClCs
- least severe
Barttin
- identified by positional cloning
- severe
different mutations in the different types of Bartter’s syndrome
type 1 - NKCC2
type 2 - ROMK
type 3 - Clc-Kb
type 4 - Barttin
type 5 - calcium receptor
what does Barttin do
Barttin helps to traffic the particular channels to the membranes
So if Barttins is not there You don’t get the channels in the membrane in the same way and they can’t be activated.
in all the renal membranes Barttin is found alongside chloride channels in the thick ascending limb of the loop of henle
It’s thought that it also modifies a sensitivity to calcium by the cell - so that calcium magnesium reabsorption can also be affected
Barttin when co expressed with ClC-K appears to diminish CLC-K sensitivity to calcium
how is Barttin/ ClC-K important in inner ear - type 4
- ClC-Ka expressed in BL membrane of marginal cells of stria vascularis cochlea and dark cells at the base of crista ampullaris of vestibular organ
- if ClC-Ka is disrupted then this will also disrupt NKCC1
- disruption of NKCC1 -> disrupts K+ balance (lowers intracellular K+) -> removes driving force of potassium into cochlear duct
- lack of potassium in endolymph of cochlear duct is associated with deafness
calcium receptor mutated in Bartters syndrome
- gain of function mutation
- autosomal dominant inheritance
- milder
- increased CaR activation/ sensitivity (basolateral membrane)
- decreased sodium transport (apical)
via a reduction in NKCC2 and ROMK protein activity on the apical membrane. this mutation also mimics the action of loop diuretics
knock out mouse model for Bartters type 1
- chemical-induced mutation in SLC12A1
-codes for NKCC2 - mouse exhibits: polyuria, hypokalaemia, metabolic alkalosis, hyper prostaglandin E2 excretion
- increased magnesium and calcium excretion
- the hypereninanaemia observed in humans is not seen
