SM 196a - Sodium Flashcards
Describe the pathophysiology of glucocorticoid-remediable aldosteronism
Basically, every time the body signals to upregulate cortisol release, aldosterone is released too
- Unequal crossing over leads to chimeric gene between aldosterone synthetase and 11-beta-hydroxylase
- The aldosterone synthetase gene falls under the control of the 11-beta-hydroxylase enzyme
- Normally 11-beta-hydroxylase regulates cortisol, not aldosterone synthetase
- The result is that ACTH secreted from the pituitary promotes aldosterone release (normally aldosterone is under the control of ANG-II)
- Results in aldosterone excess
- Remediable by glucocorticoids because increased glucocorticoids reduces ACTH secretion from the pituitary (due to feedback inhibition)
- Clinical feature, not necessarily a long-term treatment
What are the effects of Angiotensin II?
Angiotensin II works to increase blood volume
(It is a product of the RAAs pathway, activated by decreaed solute delivery/flow to the macula densa)
- Efferent arteriole vasoconstriction
- Increased Na+ reabsorption
- Proximal tubule via stimulation of the Na+/H+ exchanger
- Collecting duct via stimulation of adrenal aldosterone secretion
What percent of filtered sodium is excreted in the urine (FENa)?
Usually 0.5%
If FENa >1%, indicates a problem reabsorbing Na+
Would blocking aldosterone receptors help to treat Liddle syndrome?
Why not?
No
Liddle syndrome causes increased ENaC activity independent of aldosterone
A chronic positive sodium balance (i.e. net increase in total body sodium) will normally cause which of the following?
a. Suppression of vasopressin secretion
b. An increase in renin secretion
c. Hypernatremia
d. Weight loss
a. Suppression of vasopressin secretion
High Na+ concentration = high osmolality = release of ADH from the pituitary
However, chronic Na+ sodium balance -> chronic high blood pressure attenuates the secretion of vasopression
Which part of the kidney tubule is sensitive to Angiotensin II?
What is the effect?
Proximal tubule
Angiotensin II -> increased Na+ reabsorption in the proximal tubule
What is vasopressin?
What releases it?
Vasopressin = anti-diuretic hormone (ADH)
Promotes water reabsorpton, decreases excretion
Released from the hypothalmus
What normally regulates cortisol synthesis?
ACTH released from the pituitary
(Increased ACTH -> increasd cortisol)
What is the major re-absorber of Na+ in the Loop of Henle (TAL)?
Na+/K+/2Cl- cotransporter
Which part of the kidney tubule absorbs the most Na+?
Proximal tubule – absorbs 60-75% of all filtered sodium
- Mediated by
- Transcellular: Na/H exchange
- Paracellular: Oncotic pressure in peritubular capillaries, angiotensin II, and norepinephrine
What is the difference between volume depletion and dehydration?
Dehydration = pure water loss -> increased serum osmolality
Hypovolemia = loss of isosmotic fluid -> no change in serum osmolality
Note: if dehydration -> hypovolemia, a LOT of pure water has been lost, since only 1/12 of pure water losses are from the plasma
Sympathetic tone increases in response to low ECF
What compensatory mechanisms does this initiate?
- Renin release
- Increased Angiotensin II production
- Increased Aldosterone
- Increased Na+ reabsorption in the collecting duct
- Increased Aldosterone
- Increased Angiotensin II production
- Increased Na+ reabsorption in the proximal tubule
=> decreased urinary Na+ excretion
How does the macula densa respond to volume depletion?
Volume depletion ->
Constriction of the afferent arteriole to divert flow to the heart and brain -> decreased GFR
Pathway
- Decreased GFR
- -> Decreased NaCl delivery to the macula densa
- -> Renin release from granular cells
- -> Increased Angiotensin II
- Constriction of the efferent arteriole
- -> Restore GFR to normal
- Increased Na+ reabsoprtion in the tubules
- Stimulate Na+/H+ exchanger (PCT)
- Stimulate aldosterone secretion
(Acts on the collecting duct)
- -> Inhibition of tubuloglomerular feedback
- High NaCl delivery -> constriction (active feedback)
- Low NaCl delivery = relaxation/dilation
Atrial stretch decreases in response to low ECF
What compensatory mechanisms does this initiate?
- Decreased ANF release
- Increased Na+ reabsorption in the collecting duct
=> Decreased urinary Na+ excretion
What are the systemic effects of deficit in total body Na+?
Contraction of extracellular fluid
Hypotension (due to decreased plasma volume)
What are the systemic effects of excess total body Na+?
- Expansion of ECF
- Hypertension (due to expanded plasma)
- Edema (due to expanded interstitium)
Describe the inheritance of blood pressure
Nonmendelian, polygeninc
Influenced by the environment, but there is a strong genetic component
What are the immediate effects of reduced ECF volume?
- Decreased atrial stretch
- Increased sympathetic tone
- Decreased renal perfusion
- Decreased afferent arteriole stretch
- Decreased GFR
- Decreased NaCl delivery to Macula Densa
All of these initiate compensatory responses
Why is tuloglomerular feedback dampened in the setting of volume depletion?
Normally, tubuloglomerular feedback causes constriction of the afferent arteriole in response to high NaCl delivery to the macula densa.
Dampening tubuloglomerular feedback just means that in response to decreased NaCl delivery to the macula densa, the afferent arteriole relaxes (dilates)
What are the sensors for osmoregulation?
What do they sense?
What are the effects?
Sensor = hypothalmic osmoreceptors
Sense increased plasma osmolarity
Effect = Decreaed H2O excretion, increased H2O intake
What is the effect of a mutation in 11-beta-hydroxysteroid dehydrogenase?
- Cortisol cannot be converted to cortisone
- Cortisol mimicks aldosterone and effects increase Na+ reabsorption in the cortical collecting duct
- Results in apparent mineralocorticoid excess
What are the physiological responses to volume depletion?
-
Increased renal sympathetic activity
- Beta-1 adrenergic receptor activation
- -> Renin release from granular cells in juxtaglomerular apparatus
- Alpha-1 adrenergic receptor activation
- -> Increased proximal Na+ reabsorption (via alpha-1 adrenergic receptor activation)
- Beta-1 adrenergic receptor activation
-
Decreased right atrial stretch
- Decreased ANF (ANP) release
- -> decreased inhibition of collecting duct Na+ reabsorption
- Decreased ANF (ANP) release
- *(-> increased Na+ reabsorption)**
-
Decreased renal blood flow
- Decreased GFR
-
Angiotensin II release
- Constriction of the efferent arteriole
- -> Results in increased GFR and increased oncotic pressure in the peritubular capillaries
- This results in an increased driving force for tubular Na+ reabsorption
- Constriction of the efferent arteriole
-
Dampened tubuloglomerular feedback due to decreased NaCl delivery to the macula densa (secondary to low volume)
- When tubuloglomerular feedback is dampened, it just means that the system that constricts the afferent areteriole in response to high NaCl delivery is not active (becasue NaCl delivery is low in this case)
If your Na+ intake exceeds Na+ excretion, where does the excess sodium go?
How does your body respond?
The excess Na+ lives in the ECF
- This causes increased osmolality of the ECF
- -> Thirst
- -> Increased H2O intake
- -> Osmolality equilibrates
- -> Thirst
What are the desired outcomes of physiological compensation for decreased ECF volume?
Restore GFR
Decrease Na+ excretion
What normally regulates aldosterone synthesis?
Angiotensin II
(Increased Angiotensin II -> Increased aldosterone)
What are the sensors or volume regulation?
What do they sense?
What are the effects?
Sensors: Volume sensors, baroreceptors, macula densa
Sense EBV volume
Effects on RAAs, tubuloglomerular feedback
-
If EBV is high
- Decreased renin release
- -> Downregulates RAAs
- -> Inhibited Na+ reabsorption, promotes excretion
- Vasoconstriction of the efferent arteriole
- Decreased renin release
-
If EBV is low
- Increased renin release
- -> Upregulates RAAs
- -> Increased Na+ reabsoprtion, decreased excretion
- Vasodilation of the efferent arteriole
- Increased renin release
What causes Liddle syndrome?
An activating mutation in the epithelial sodium channel ENaC
-> increased Na+ reabsorption (even if inappropriate physiologically)
A 70 year old woman with chronically impaired kidney function develops swollen feet and ankles (edema) and a blood pressure of 180/100 (elevated). Which statement best explains the edema and hypertension?
- the patient has been standing too much and is overly anxious
- she has expansion of total body water
- she has hypoosmolality of extracellular fluid
- she has increased interstitial fluid and plasma volume
- her probably has proteinuria that is causing inflammation of peripheral capillary beds
D. she has increased interstitial fluid and plasma volume
What are the mediators of Na+ reabsorption in the proximal tubule?
- Higher oncotic pressure in the peritubular capillaries than in the tubule
- Angiotensin II
- Norepinephrine
What is the inheritance of glucocorticoid-remediable aldosteronism?
Autosomal dominant
Which of the following physiological parameters is NOT affected by the regulation of renal sodium excretion?
a. Plasma volume
b. Interstitial volume
c. Arterial blood pressure
d. Plasma sodium concentration
e. Cardiac output
d. Plasma sodium concentration
Regulating renal Na excretion regulates ECF volume, not the concentration of Na+ in the blood. We would assume that positive Na+ balance in the plasma evokes thirst, in order to preserve ECF osmolality
What causes apparent mineralocorticoid excess?
Mutation in the 11-beta-hydroxysteroid dehydrogenase
- Cortisol cannot be converted to cortisone
- Cortisol mimicks aldosterone and effects increase Na+ reabsorption in the cortical collecting duct
- Results in apparent mineralocorticoid excess
NaCl delivery to the macula densa decreases in response to low ECF
What compensatory mechanisms does this initiate?
- Increased renin release
- Increased Angiotensin II production
- Efferent arteriole constriction
- Increased filtration fraction
- Increased peritubular oncotic pressure
- => Decreaed urinary Na+ excretion
- Efferent arteriole constriction
- Increased Angiotensin II production
- Decreased tubuloglomerular feedback
- Afferent arteriole relaxation (dilation)
- Afferent arteriole relaxation (dilation) + efferent arteriole constriction
- => Restoration of GFR
________ directly increases proximal tubular Na+ reabsorption, while ________ directly increases collecting duct Na+ reabsorption
Angiotensin II** directly increases proximal tubular Na+ reabsorption, while **Aldosterone directly increases collecting duct Na+ reabsorption
Describe the presentation of glucocorticoid-remediable aldosteronism
Early onset, severe hypertension
Hypertension is suppressible by glucocorticoids
Which part of the kidney tubule is sensitive to aldosterone?
What is the effect?
Collecting duct
Aldosterone -> increased Na+ reabsorption in the collecting duct
What causes pseudohypoaldosteronism I?
LOF mutations in ENaC
-> Decreased Na+ reabsorption -> hypotension
Aldosterone is very high to promote Na+ reabsorption, but ENaC is not responsive
How does blood pressure affect ADH signaling?
Chronic high blood pressure attenuates the secretion of ADH
Remember, that chronic positive Na+ balance -> increased ECF volume to maintain osmolality -> increaed blood pressure
