3b - Physiology for Mendelian Forms of HTN Flashcards
what is the funtion of the principal cells of the late distal tubule and cortical collecting duct?
Reabsorb Na+, secrete K+
Regulated by aldosterone.
Water permability regulted by ADH.
What drugs act on the principal cells of the late distal tubule and cortical collecting duct? What is their effect?
Reabsorption of sodium and secretion of potassium via the ENaC channel is blocked by K-sparing diuretics such as amiloride and triamterene.
Where does aldosterone act and what is it’s function?
Acts in the principal cells of the late distal tubule and collecting duct.
Increase Na reabsorption and K secretion.
How does the syndrome of apparent mineralocorticoid excess (AME) present?
Low birth weight, failure to thrive, severe HTN in early childhood, extensive organ damage and renal failure.
What are clinical findings in a patient with syndrome of apparent mineralocorticoid excess (AME)?
- HTN
- Hypokalemia
- Metabolic alkalosis
- Low plasma renin
- Low plasma and urine aldosterone levels
Findings similar to primary aldosteronism: differential elevated plasma aldosterone levels.
How would you diagnose syndrome of apparent mineralocorticoid excess (AME)? What mutation causes this?
These patients have an aut recessive loss of function mutation in 11B-HSD2 which inhibits them from converting cortisol to its inactive form cortison.
You can diagnose this by seeing a very low or undetectable urinary free cortisone and confirm with sequencing of the 11B-HSD2 gene.
This is rare and usually results from a consanguineous relationship.
What is the result of having a defective 11B-HSD as seen in syndrome of apparent mineralocorticoid excess (AME)?
Because cortisol can’t be converted to its inactive form. More is available to bind the mineralocorticoid receptor, resulting in mineralocorticoid excess.
This results in HTN and hypokalemia.
What is Liddle Syndrome? What is the clinical presentation?
Aka pseudoaldosteronism.
- HTN-young onset, severe
- Hypokalemia
- Metabolic alkalosis
- Low plasma renin activity, findings similar to other mineralocorticoid excess syndromes
- Low plasma and urinary aldosterone
What mutation results in Liddle syndrome? How would you confirm the diagnosis?
Gain of function mutation in the renal epithelial sodium channel leading to constituitive expression.
Cansequence SCNN1A, SCNN1B, and SCNN1G to confirm.
Resultsin increased absorption of sodium, leading to HTN.
What is the treatment of apparent mineralocorticoid excess? What is the prognosis?
- Block mineral corticoid receptor with an aldosterone antagonist (spironolactone, eplerenone)
- Sodium channel blockers (amiloride/triamterene)
- Potassium supplementation
- Dexamethasone for ACTH supression (reduces endogenous cortisol production)
Prognosis is usually poor becuase of advanced progression of the disease at the time of diagnosis.
What is the treatment of Liddle Syndrome? What is the prognosis?
Agents that decrease sodium channel activity: amiloride and triamterene
With treatment prognosis is good.
Without treatment CV and renal complications from uncontrolled HTN often occur.
How do AME and liddle syndromes differ?
They are very similar but are caused by different muations and are inherited differently.
AME is caused by the inability to convert cortisol to cortison and is a loss of function autosomal recessive mutation.
Liddle syndrome is caused by a constituitively active ENaC channel leading to persistant unregulated reabsorption of sodium and secretion of K. It’s caused by an autosomal dominant gain of function mutation.
What occurs in the thick ascending loop of henle?
Reabsorption of 25% of filtered Na+ by the Na/K/2Cl transporter.
Lumen positive potential drives paracellular resorption of sodium, potassium, magnesium, and cvalcium.
Impermeable to water, dilutes tubular fluid.
What are the transport characteristics of the early distal tubule?
Reabsorbs Na, Cl, Ca2+, and Mg2+.
Not permeable to water.
Thiazide-sensitive.
What are two renal tubular salt-wasting disorders?
Gitelman syndrome and Bartter syndrome (types 1, 2, and 3).
Both have impairment of a transported involved in Na and Cl reabsorption.
What is the defect location in Bartter syndrome? What is the presentation and symptoms?
Ascending limb of the loop of henla ()site of loop diuretic action)
Early onset: prenatal, infancy, childhood.
Symptoms: severe hypotension, growth and developmental delays, and polyuria/polydipsia
What is the molecular basis of Bartter syndrome? What is the inheritance?
Concentrating capacity of this region is severely impared by a loss of function autosomal recessive mutation.
What is the defect location in Gitelman syndrome? When is the onset and what are the symptoms?
Distal tubule (site of thiazide diuretics)
Presents in adolescence/adulthood.
- May be asympomatic, hypotension
- Cramping of the arms and legs, fatigue
- Polyuria and nocturia (waking up during the night to go to the bathroom)
What do both Bartter syndrome and Gitelman syndrome result in?
Decrease Na reabsorption leading to salt wasting.
This causes hypotension, renin secretion, and increased aldosterone levels.
- This increases the ENaC channel causing Na and water reabsorption and K secretion (leading to hypokalemia)
- This also results in hydrogen ion secretion which causes metabolic alkalosis
