Changes in Plasma Osmolarity and Control of Serum Calcium/Stone Formation Flashcards
What happens when water intake < excretion?
Plasma osmolarity increases
What happens when water intake > excretion?
Plasma osmolarity decreases
What happens to the concentration of urine as the amount produced increases?
It decreases
What maintains body fluid osmolarity?
Osmoregulation
What is body fluid osmolarity maintained at?
275-295mOsm/kg
How do disorders of water balance manifest?
As changes in the body fluid osmolarity
How do disorders of Na+ balance manifest?
Changes in volume
Draw a graph showing the relationship between urine output and concentration of urine
What detects changes in plasma osmolarity?
The hypothalamic osmoreceptors
Where are the hypothalmic osmoreceptors located?
In the Organum Vasculom of the Laminae Terminalis (OVLT)
Where is the OVLT situated?
Anterior and ventral to the third ventricle
What epithelium does the OVLT have?
Fenestrated, leaky
Why does the OVLT have a fenestrated, leaky epithelium?
To exposure it directly to the systemic circulation
What happens when a change in plasma osmolarity is sensed?
The OVLT coordinates responses via two different efferent pathways
What do the efferent pathways work to do when a change in plasma osmolarity is sensed?
One concentrates urine, and one decreases thirst
At what level of dehydration do you feel thirsty?
~10%
How does the efferent pathway concentrating urine exert its effect?
It affects ADH, leading to increased renal water secretion
What is the effector for the ADH efferent pathway?
The kidney
What is the effector for the thirst efferent pathway?
Brain; drinking behaviour
What happens if plasma osmolarity increases due to a predominant loss of water?
Osmoreceptors in the hypothalamus (OVLT) initiate the release of ADH from the posterior pituitary
At what increase in plasma osmolarity due to a predominant loss in water would osmoreceptors stimulate ADH release?
1% change
What affect does decreased osmolarity have on ADH secretion?
It inhibits it
Describe an ADH molecule
Small peptide, 99AA’s long
What does ADH act on?
The kidney
What does ADH act on the kidney to do?
Regulate the volume and osmolarity of the urine
How does ADH regulate the volume and osmolarity of the urine?
By increasing the permeability of the kidneys to water and urea
How does ADH increase the permeability of the kidney to water?
By the addition of the water channel Aquaporin-2 to the apical membrne of the nephron’s collecting duct
What does the ADH driven addition of Aquaporin-2 allow for?
The reabsorption of water to decrease plasma osmolarity
Do apical membranes contain Aquaporin 2 in the absence of ADH?
No
What happens when ADH is released?
With respect to Aquaporin 2
It is inserted into the membrane
What happens to Aquaporin 2 when ADH is removed?
The channel is retrieved from the apical membrane
How is Aquaporin 2 retrieved from the apical membrane?
Via endocytosis
What does the basolateral membrane always contain?
Aquaporin 3 and 4
What is the result of the basolateral membrane always containing Aquaporin 3 and 4?
It is constantly permeable to water
What is the result of the basolateral membrane always being permeable to water?
Any water that enters across the apical membrane is able to pass into the peritubular blood
What does ADH cause the reabsorption of?
Urea
How does ADH cause the reabsorption of urea?
It increases the permeability of the medullary part of the collecting duct to urea
What does the reabsorption of urea in the medullary part of the collecting duct cause?
Water to follow
What does the rise in urea concentration in the tissues as a result of urea reabsorption in the medullarly part of the collecting duct cause?
It to passively move down its concentration gradient into the ascending limb
Is the ascending limb permeable to urea?
Yes
Is the ascending limb permeable to water?
No
What happens once urea has moved down its concentration gradient into the ascending limb?
It passes back into the collecting duct, where it is reabsorbed into the medullary portion, and more water follows
What is the overall effect of ADH on urea?
It causes urea to be recycled
What is SIADH?
Syndrome of Inappropriate Anti-Diuretic Hormone Secretion
What happens in SIADH?
The secretion of ADH is not inhibited by the lowering of blood osmolarity (negative feedback is removed)
What is the result of the secretion of ADH not being inhibited by the lowering of blood osmolarity?
Excessive amounts of water is retained
What does excessive water retention cause in SIADH?
- Blood osmolarity drops
- Hyponatremia
What is hyponatremia?
Low blood Na+ concentration
What are the symptoms of hyponatremia?
- Nausea
- Vomiting
- Headache
- Confusion
- Lethargy
- Fatigue
- Appetite loss
- Restlessness
- Irritability
- Muscle weakness
- Spasms
- Cramps
- Seizures
- Decreased consciousness or coma
How can hypernatremia be treated if it comes about because of SIADH?
With ADH Receptor Antagonists
What is the osmotic gradient at the cortico-medullary border?
None
What is the osmotic graient of the medullary intersticium?
Hyperosmotic up to 100mOsmol/Kg at the papilla
What happens to the gradient of osmolarity as you descend?
It increases
What sets up the osmotic gradient?
The active transport of NaCl out of the TAL and the recycling of urea
Why is the action of the TAL crucial?
It removes solute without water, diluting the filtrate and increasing intersticium osmolarity
How can NaK2Cl transporters in the TAL be blocked?
With a loop diuretic
Give an example of a loop diuretic that can block NaK2Cl transporters in the TAL
Furosemide
What happens if you block the NaK2Cl transporters in the TAL?
The medullary intersticium becomes isosmotic and large amounts of dilute urine is produced
What does the Loop of Henle act as to set up the osmotic gradient?
A counter current multiplier
How does the Loop of Henle act as a counter current multiplier?
- Tubule filled initially with isotonic fluid
- Na+ ions are pumped out of the ascending loop, raising the osmotic pressure outside the tubule and lowering it inside
- Fresh fluid enters the glomerulus, and enters the descending limb. As the descending limb is permeable to water, it leaves via osmosis to raise the osmotic pressure inside the descending tubule to 400mOsmol/L
- More fluid enters from the glomerulus, pushing the concentrated fluid into the ascending limb
- The Na+ pump then produces another 200mOsmol/L gradient across the membrane, but it started with a more concentrated solution (400sOsmol/L), so external osmolarity rises to 500mOsmol/L
- Fresh fluid again enters; water leaves via osmosis until the osmotic pressure in the descending tubule is 500mOsmol/L
- This is then pushed into the ascending limb, where the Na+ pump produces yet another 200mOsmol/L gradient, raising the interstitial osmolarity to 700mOsmol/L
- The final gradient will be limited by the diffusion process
How are Na+ ions pumped out of the ascending loop?
Na/K/Cl co-transporter
What is the max concentration difference inside the Loop of Henle and out?
200mOsmol/L
Draw a series of diagrams illustrating the Loop of Henle acting as a counter current multiplier
What is required to make the concentration gradient that the loop of Henle sets up last long?
The Vasa Recta
What are Vasa Recta?
Blood vessels that run alongside the loops, but with opposite flow direction
What does the counter current flow between the Loop of Henle and the Vasa Recta allow?
Maintenance of the concentration gradient
What happens to isosmotic blood in the descending limb of the vasa reta?
It inters the hyperosmotic milieu of the medulla
What is true of the milieu of the medulla?
There is a high concentration of ions (Na+, Cl-, Urea)
What happens once the isosmotic blood in the descending limb of the vasa recta enters the hyperosmotic milieu of the medulla?
The ions from the milieu of the medulla diffuse into the vasa recta, and water diffuses out
What happens to the osmolarity of the blood in the vasa recta?
It increases as it reaches the tip of the hairpin loop
What is true of the blood in the vasa recta as it reaches the tip of the hairpin loop?
It is isosmotic with the medullary intersticium
What is true of blood ascending towards the cortex?
It will have a higher solute content than the surrounding intersticium
What is the result of the blood ascending towards the cortex having a higher solute content than the surrounding intersticium?
Solute moves back out
Where does water move from the descending limb?
To the loop of Henle
What is the overall result of the U shape of the vasa recta allowing it to act as a counter current exchanger?
Although there is a large amount of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid
What does the U shape of the vasa recta allow?
It to act as a counter current exchanger
What is the contribution of the vasa recta to medullary hyperosmolarity?
It does not create it, but prevents it from being dissipated
Draw a diagram illustrating how counter current exchange in the vasa recta works
What critical roles does calcium play in cellular processes?
- Hormone secretion
- Nerve conduction
- Inactivation/activation of enzymes
- Muscle contraction
- Exocytosis
What is the result of calcium playing a critical role in many cellular processes?
The body must very carefully regulate the plasma concentration of free ionised calcium and maintain free plasma [Ca2+] within a narrow range
What is free ionised calcium?
The physiologically active form of the metal
What range must free plasma calcium concentration be maintained at?
1.0 - 1.3mmol/L
What % of plasma calcium exists as the free ionised species?
45%
What % of plasma calcium exists protein bound?
45%
What is plasma calcium protein bound to?
80% bound to albumin
What % of plasma calcium exists complexed?
10%
What is plasma calcium complexed with?
Citrates, phosphate etc
What is the absorption of calcium in the intestines under the control of?
Vitamin D
How much dietary calcium is absorbed in the intestines?
20-40% (25mmol)
How much calcium is secreted back into the gut?
2-5mmol
When does calcium absorption in the intestines increase?
- Growing children
- Pregnancy
- Lactation
When does calcium absorption in the intestines decrease?
With advancing age
What reduced the absorption of calcium in the intestines?
Complexing calcium
What can calcium be complexed with to reduce its absorption?
Oxalates
How much calcium to the kidneys filter?
250mmol per day
How much calcium is reabsorbed in the kidneys?
95-98%
How much calcium is excreted in urine?
<10mmol/day
What % of calcium is reabsorbed in the PCT?
65%
What is calcium reabsorption in the PCT associated with?
Na+ and water uptake
What % of calcium is reabsorped in the loop of Henle?
20-25%
What % of calcium is reabsorped in the DCT?
10%
What is calcium reabsorption in the PCT under the control of?
PTH
How does the body obtain vitamin D?
Absorbed in the gut or synthesised in the skin in the presence of sunlight
What is vitamin D converted to?
Calciferol
Where is vitamin D converte to Calciferol?
In the liver
Why is vitamin D converted to Calciferol in the liver?
To increase its short half-life
What does parathyroid hormone (PTH) do?
Regulates the conversion of Calciferol in the kidney to its active form, Calcitriol
What is Calcitriol?
The active form of vitamin D
How does Calcitriol work?
By binding to Calcium in the gut to increase in absorption
How does PTH affect calcium levels directly?
By increasing its release from bone and its reabsorption in the PCT of the kidney
What does PTH decrease the reabsorption of?
Phosphate and bicarbonate
Why does PTH decrease the reabsorption of phosphate and bicarbonate?
If they are present in the blood with Calcium, stones will form
What are the types of vitamin D?
- Vitamin D2
- Vitamin D3
How does vitamin D2 enter the body?
It is absorbed by the gut
What is action of vitamin D2?
None- prohormone
How does vitamin D3 enter the body?
Skin (UV light)
What is the action of vitamin D3?
None- prohormone
Where is Calciferol produced?
Liver
What is Calciferol produced from?
The first hydroxylation of vit D
What is the action of Calciferol?
None- prohormone
Where is Calcitriol formed?
Kidney
What is Calcitriol produced from?
2nd Hydroxylation of Vit D
What is the action of calcitriol?
Increases Ca2+ absorption
Where is parathyroid hormone produced?
Parathyroid gland
How do calcium levels regulate PTH?
Via negative feedback
What are the causes of hypercalcaemia?
- Primary hyperparathyroidism
- Haemotological malignancies
- Non-haemotological malignancies
What is the prevalance of primary hyperparathyroidism?
~1/1,000 of the general population
What does hypercalcaemia of malignancy come about due to?
The production of Parathyroidhormone-Related Peptide (PTHrP)
Why does PTHrP cause hypercalcaemia of malignancy?
Because it has AA homology with the active portion of PTH and works to increase plasma Ca2+ concentration
What are the categories of symptoms of hypercalcaemia?
- Gastrointestinal
- Cardiovascular
- Central Nervous System
What are the gastrointestinal symptoms of hypercalcaemia?
- Anorexia
- Nausea/vomiting
- Constipation
- Acute pancreatitis
How commonly does hypercalcaemia cause acute pancreatitis?
Rarely
What are the cardiovascular symptoms of hypercalcaemia?
- Hypertension
- Shortened QT interval on ECG
- Enhanced sensitivity to digoxin
- Renal
- Polyuria
- Polydipsia
- Occasional nephrocalcinosis
What are the CNS symptoms of hypercalcaemia?
- Cognitive difficulties and apathy
- Depression
- Drowsiness
- Coma
What are the general measures in hypercalcaemia management?
- Hydration
- Loop diuretics
What is the purpose of hydration and loop diuretics in hypercalcaemia management?
Increase Ca+ excretion
What are the specific measures in hypercalcaemia management?
- Bisphosphonates
- Calcitonin
What is the purpose of bisphosphonates in hypercalcaemia management?
Inhibit the breakdown of bone
What is the purpose of Calcitonin in hypercalcaemia management?
Opposes the action of PTH
What is important in hypercalcaemia management?
Treat underlying condition
What % of men develop renal stones in their lifetime?
20%
What % of women develop renal stones in their lifetime?
5-10%
What % of all renal tract stones are made of calcium?
70-80%
What factors are involved in the formation of calcium renal stones?
- Low urine volume
- Hypercaluria
- Low urine pH
At what urine pH to calcium renal stones form?
<5.47
What does the mechanism of stone formation involve?
The super-saturation of urine with calcium oxalate
What does conservative management of renal stones include?
- Increasing fluid intake
- Restricting dietary oxalate and sodium
- Considering the dietary restriction of calcium and animal protein
