23-02-23 - Producing a concentrated or dilute urine Flashcards
Learning outcomes
- Understand the sites of water reabsorption along the nephron and how these can change. Understand the sites of NaCl reabsorption along the tubule.
- Describe the transport mechanisms in the Loop of Henle including the: Thin Descending Limb, Thin Ascending Limb and Thick Ascending Limb.
- Understand the mechanisms underpinning a hyperosmotic medullary interstitium with reference to the counter current multiplier mechanism and the counter current exchange mechanism (vasa recta).
- Describe how the permeability of urea changes in the tubule and how this further increases the osmolality of the medullary interstitium.
- Describe the transport processes in the distal tubule and collecting duct.
- Define the key mechanisms by which the kidneys can produce either a dilute or a concentrated urine.
Learning outcomes
- Understand the sites of water reabsorption along the nephron and how these can change. Understand the sites of NaCl reabsorption along the tubule.
- Describe the transport mechanisms in the Loop of Henle including the: Thin Descending Limb, Thin Ascending Limb and Thick Ascending Limb.
- Understand the mechanisms underpinning a hyperosmotic medullary interstitium with reference to the counter current multiplier mechanism and the counter current exchange mechanism (vasa recta).
- Describe how the permeability of urea changes in the tubule and how this further increases the osmolality of the medullary interstitium.
- Describe the transport processes in the distal tubule and collecting duct.
- Define the key mechanisms by which the kidneys can produce either a dilute or a concentrated urine.
What is osmolarity a measure of?
What is it defined as?
What do these contribute to?
What is molarity?
What do we need to consider with molarity?
What is an example of where this is important?
- Osmolarity is a measure of solute concentration
- It is defined as the number of osmoles (Osm) of a solute per litre (L) of solution (Osm/L)
- These contribute to the osmotic pressure of a solution
- Molarity is the number of moles of a substance in a volume (mol/L)
- With molarity, we need to consider if the solute dissociates:
- 1 mol/L glucose (180g in 1L) = 1 Osm/L
- 1 mol/L of NaCl (58.5g in 1L) = 2 Osm/L
- NaCl dissociates into ions in water
What is osmolarity and osmolality?
What is an advantage of each?
How are each measured/calculated?
Are they each equal to eachother?
What is the normal osmolality of blood plasma?
- Osmolarity:
- Number of osmoles of solute per litre of solution (Osm/L)
- More practical
- Calculated from blood tests e.g. (Na+ + K+ + glucose + urea)
- Osmolality:
- Number of osmoles of solute per kg of solvent (Osm/kg)
- More accurate (e.g. if you heat a solution - volume expands, weight remains the same)
- Measured by osmometer (in labs)
- Osmolarity and osmolality should be roughly equal (otherwise - “osmolar gap”)
- The normal osmolality of blood plasma is ~290 mOsm/kg
What is the interstitial fluid of renal capillaries almost identical in composition to?
When will tubular fluid change composition?
When will tubular fluid be near identical to plasma?
- The interstitial fluid that bathes cells (e.g. epithelia lining tubule and endothelial cells lining capillaries) is almost identical to plasma in terms of composition
- The tubular fluid will change composition as it travels along the tubule
- Immediately after filtration, tubular fluid it is also near identical to plasma
What should water intake match in the body’s steady state?
What are 3 sources of water input?
What are 4 sources of water output?
What is the major route of water loss in the body?
What does this play a central role in?
What do the kidneys do to compensate for abnormal water intake/excretion?
- In the steady state, water intake and output must be equal
- 3 sources of water input:
1) Ingested fluids - 1,200ml
2) Ingested food - 1,000ml
3) Metabolism – 300ml - Total – 2500ml
- 4 sources of water output:
1) Urine - 1,500ml (regulated)
2) Faeces - 100ml
3) Skin/sweat - 550ml
4) Exhaled air - 350ml - Total – 2500ml
- The major route of water loss is usually via the kidneys
- Play a central role in regulating water balance
- The kidneys adjust water output to compensate for abnormal (e.g. high or low) water intake or excretion
What is the excreted amount of solute in a normal diet?
What volume of urine is this normally dissolved?
How can high/low intake/excretion dilute solute to different degrees?
- With consumption of a normal diet, the excreted amount of solute remains ~600 milliosmoles/day
- Normally this would be dissolved in a daily urine output of ~1.5L
- Therefore, depending on water intake/excretion, these 600 milliosmoles will be diluted to different degrees:
- 600 milliosmoles dissolved in 1.5L urine
- Urine osmolality is 450 mOsm/kg
1) High intake of water:
* Need to get rid of water, urine volume greater and more dilute
* E.g. 600 milliosmoles in 15 L urine, which is 40 mOsm/kg
2) Low intake of water / excessive sweat or stool
* Need to conserve water, urine volume reduced and concentrated
* E.g. 600 milliosmoles in 0.5 L urine, which is 1,200 mOsm/kg
What do the kidneys do when there is excess water in the body?
What are 2 changes seen in the kidneys if we drink 1 lite of water?
What controls water excretion under steady-state conditions?
- In the face of excess water in the body, the kidney excretes H2O but without compromising reabsorption of solutes
- 2 changes seen in the kidneys if we drink 1 lite of water:
1) Rapidly increase urine flow and reduce osmolality (so a lot of dilute, hypo-osmotic, urine)
2) Urinary solute excretion does not change much, so plasma osmolality remains stable
- Under steady-state conditions, kidneys control water excretion independently of solute excretion
What 2 places does water transport in the nephron occur?
Under what conditions can water transport in the nephron occur in different places?
- 2 places water transport in the nephron occur:
1) Proximal tubule
2) Thin descending limb of the Loop of Henle - Water transport can also occur under certain conditions in the:
1) Cortical collecting duct
2) Medullary collecting duct - This is only when arginine vasopressin (AVP), also known as anti-diuretic hormone (ADH), is released.
Why does solute need to be separated from water in the nephron?
Where does this occur in the nephron?
Where is H2O reabsorbed in the nephron?
Where is NaCl reabsorbed in the nephron?
- The ability of the kidneys to excrete a urine of varying osmolality requires that solute be separated from water in the nephron
- This occurs in the Loop of Henle
- Only H2O (no NaCl) reabsorption in the thin descending limb
- Only NaCl (no H2O) reabsorption in the thin ascending limb and thick ascending limb
What % of H2O and Na+ are reabsorbed in the proximal tubule?
What kind of reabsorption is this?
When does this remain true?
- ~65% of H2O and Na+ are reabsorbed in the proximal tubule
- This reabsorption iso-osmotic e.g. the osmolality of the tubular fluid (ultrafiltrate) is equal to the interstitial fluid outside of the tubules (~300 mOsm/kg)
- This remains true regardless of requirements for water excretion
What % of nephrons are juxtamedullary nephrons?
What do they play an important role in?
Where do they stretch to?
Where do the collecting ducts of both types of nephrons join?
What is the Loop of Henle of the juxtamedullary nephrons surrounded by?
- 15 % are juxtamedullary nephrons and play an important role in creating conditions which allow concentration of the urine
- These stretch deep into the medulla, right down to the papilla
- The collecting ducts of both types of nephrons will join together and descend down the medulla, to the papilla where urine drains into a calyx
- The Loop of Henle of the juxtamedullary nephrons are surrounded by the vasa recta
Thin descending limb of LOH.
How is H2O reabsorbed in the thin descending limb of the loop of Henle?
What is required for this to happen?
What is transcellular transport here impermeable to?
- Thin descending limb of LOH
- H2O is reabsorbed via Aquaporin1 water channels in a transcellular manner in the thin descending limb of the LOH
- These channels are open, but H2O still requires an osmotic gradient to move
- Transcellular transport here is impermeable to NaCl
Thin ascending limb of LOH.
How does transport occur in the thin ascending LOH?
Which 2 substances are transported here?
What is paracellular transport here impermeable to?
- Thin ascending LOH
- Transport in the thin ascending LOH is only via passive paracellular route:
1) Na+
2) Cl- - Paracellular transport here is impermeable to H2O
Thick ascending limb of LOH – K+.
How are electrochemical gradients generated in the thick ascending LOH?
How is K+ transported in the basolateral membrane?
How can K+ also move through the apical membrane?
What does this maintain an electrical gradient for?
- Thick ascending limb of LOH – K+
- In the thick ascending LOH, basolateral Na+/K+ ATPase which will generate electrochemical gradients
- There are Leak K+ channel in basolateral membrane
- K+ can also leave the cell across the apical membrane via ROMK (renal outer medullary K+ channel)
- This maintains an electrical gradient important for other paracellular transport
Thick ascending limb of LOH – Na+ and K+.
How does Na+ enter and exit cells in the Thick ascending limb of LOH?
How does K+ exit?
- Thick ascending limb of LOH – Na+ and K+
- Na+ enters cells, down it’s electrochemical gradient via the Na+-K+-Cl- co-transporter (NKCC2), which co-transports K+ and 2x Cl
- Na+ is pumped out across basolateral membrane via Na+/K+
K+ exits through either the NKCC2 co-transporter or the K+ channel in the Thick ascending limb of LOH
Thick ascending limb of LOH – Cl-, Na+, Mg2+, Ca2+.
How does Cl- move across the basolateral membrane?
- Thick ascending limb of LOH – Cl-, Na+, Mg2+, Ca2+.
- How can Na+ be reabsorbed here? What other 2 substances can be rebsorbed here? What is this due to?
- Cl- moves across basolateral membrane via a Cl- channel
- Na+ can also be reabsorbed via the paracellular pathway
- This is also how Mg2+ and Ca2+ can be reabsorbed
- This is due to the gradient from ROMK K+ channel
Thick ascending limb of LOH. Where have Na+ and Cl- been reabsorbed from?
Why can’t H20 be reabsorbed in this portion of the nephron?
- Thick ascending limb of LOH
- Na+ and Cl- have been reabsorbed from the tubular fluid into the interstitial fluid
- H2O cannot be reabsorbed as this portion of the nephron is impermeable to H2O
What is the osmolality of the tubular fluid entering the thin descending limb of the LOH?
What happens to the tubular fluid as it travels along the tubule?
Where is H2O reabsorbed?
How does this affect the tubular fluid?
Where is NaCl reabsorbed?
How will this affect the tubular fluid?
What do we need to understand during this process?
- The tubular fluid entering the thin descending limb of the Loop of Henle is 300 mOsm/kg H2O
- As the ultrafiltrate (tubular fluid) travels along the tubule, the transport of H2O or Na+, Cl will alter the osmolality
- H2O is reabsorbed in thin descending limb – concentrating the tubular fluid
- NaCl is reabsorbed in the thin and thick ascending limb – diluting the tubular fluid 300
- We need to understand the osmotic gradients that are involved during this process
Describe the 7 steps in the counter-current multiplier mechanism in the LOH
- 7 steps in the counter-current multiplier mechanism in the LOH:
1) The “first” time the tubular fluid enters the Loop, it will travel all the way to the thick ascending limb (TAL), because there are no gradients enabling passive transport.
2) In the TAL – Na+ and Cl+ are reabsorbed into the medullary interstitium via NKCC2, generating an osmotic gradient ~200mOsm between tubular fluid and interstitium.
3) The interstitium is now hyperosmotic (400mOsm) because of the extra NaCl, and this osmotic gradient enables passive reabsorption of H2O in the earlier descending limb. The movement of water out of the tubular fluid, increases the osmolality of the tubular fluid in the descending limb. H2O will move out of the tubule and equilibrate to the osmolality of the medullary interstitium.
4) Tubular fluid moves round the loop and fresh fluid from the proximal tubule (300mOsm) enters the Loop.
5) NaCl is reabsorbed in the thin and thick ascending limb (thin now possible because of osmotic gradient established). So there is always a gradient of 200mOsm from the tubular fluid to the medullary interstitium.
6) The fluid moving down the descending limb will equilibrate to the osmolality of the medullary interstitium
7) This keeps getting repeated, establishing a greater and greater gradient the further the loop stretches down the medulla – e.g. more H2O removed in the descending limb and more NaCl reabsorbed in the thick ascending limb. It is a counter current multiplier
What is the osmolality of the tubular fluid leaving the thick ascending limb compared to plasma?
What does this mean the counter current multiplier mechanism does do?
What does the counter-current multiplier mechanism do?
What is this important for?
- The tubular fluid leaving the thick ascending limb, moving into the distal convoluted tubule is actually hypo-osmotic (compared to plasma) at ~100 mOsm/kg.
- So, the counter current multiplier mechanism does not concentrate the urine
- The counter current multiplier mechanism generates a hyperosmotic medullary interstitium
- This will be key for the concentrating of urine in the collecting ducts once the tubule descends back down the medulla
Distal convoluted tubule (DCT)
What 3 transporters/channels are in the basolateral membrane of the distal convoluted tubule (DCT)?
What co-transporter is in the apical membrane of the distal convoluted tubule (DCT)?
How do Na+ and Cl- move in the DCT?
What substance is not transported here?
- Distal convoluted tubule (DCT)
- 3 transporters/channels in the basolateral membrane of the distal convoluted tubule (DCT):
1) Na+/K+ ATPase
2) leak K+ channel
3) Cl- channel - Na+-Cl- co-transporter (NCC) in the apical membrane of the distal convoluted tubule (DCT)
- Na+ and Cl- moving via transcellular route in the DCT
- No H2O transport occurs here
Collecting duct.
What 3 types of transporters/channels are on the apical surface of the collecting duct?
What 3 types of transporters/channels are on the basolateral surface of the collecting duct?
How is H2O reabsorption driven?
When will H20 reabsorption occur in the collecting duct?
What 3 substances are transported via transcellular transport in the collecting duct?
What substances moves via the paracellular pathway in the collecting duct?
- Collecting duct
- 3 types of transporters/channels are on the apical surface of the collecting duct:
1) ROMK also allows apical K+ exit
2) ENaC allows apical entry of Na+
3) H2O entry via Aquaporin 2 - 3 types of transporters/channels are on the basolateral surface of the collecting duct:
1) Na+/K+ ATPase
2) leak K+
3) H2O entry via Aquaporin 3 and 4 - Osmotic gradient drives H2O reabsorption via Aquaporins
- H2O reabsorption only occurs in the collecting duct if AVP (ADH) is released
- Na+, K+ and H2O transport is transcellular in the collecting duct
- Cl- moves via a paracellular pathway in the collecting duct
What is the osmolality of tubular fluid entering the distal convoluted tubule (DCT)?
What happens to tubular fluid as it moves along the DCT?
Where is NaCl further absorbed?
What happens when water deprivation occurs?
What is key to driving this movement?
- The osmolality of the tubular fluid entering the distal convoluted tubule (DCT) is ~100 mOsm/kg H2O
- As the ultrafiltrate (tubular fluid) travels along the DCT, only NaCl will be absorbed – diluting the tubular fluid
- NaCl is then further reabsorbed in the cortical collecting duct (CCD) and a very small amount in the medullary CD – further diluting 300
- During water deprivation, AVP will be released and stimulates H2O reabsorption in the collecting duct – the osmotic gradient established in the medullary interstitium is key to driving this movement
What does the reabsorption of NaCl in the counter current multiplier mechanism not full account for?
What does urea contribute to the osmolality of?
What does the movement of urea depend on?
Does it move actively or passively?
- The reabsorption of NaCl in the counter current multiplier mechanism doesn’t account for the full extent of the hyperosmotic medullary interstitium
- Urea contributes to 40-50% of the osmolality (500-600 mOsm/kg) of the renal interstitium when maximally concentrating urine
- Movement of urea is also very important
- It depends where transport is possible along the tubule
- Urea moves passively (e.g. down it’s chemical gradient)
Describe the movements and concentrations of urea in the:
1) Proximal tubule
2) Thin descending limb LOH
3) Medullary CD
- Movements and concentrations of urea in the
1) Proximal tubule
* Movement occurs through solvent drag through tight junctions
* Higher concentration of urea in tubule
2) Thin descending limb LOH
* Transcellular secretion of urea (UT-A2)
* Higher concentration of urea in interstitium (from CD)
3) Medullary CD
* Transcellular reabsorption of urea (UT-A1 or UT-A3)
* Higher concentration of urea in tubule
* This effectively “recycles” to the LOH
Describe the 6 steps in the reabsorption/secretion of urea in the kidney tubule
- 6 steps in the reabsorption/secretion of urea in the kidney tubule:
1) Urea is freely filtered
2) ~50 % is reabsorbed in the proximal tubule
3) However, 50 % is secreted into the thin descending and ascending limbs (due to parallel reabsorption pathway in the medullary CD, “recycling”)
4) None is transported in the DCT/CCD as they are impermeable to urea
5) Urea is reabsorbed from the medullary CD into the interstitium, raising the conc. of urea in the interstitial fluid, raising the osmolality and promoting secretion in the LOH
6) Remainder is excreted into urine
What does the vasa recta surround?
What is their role?
How is it different from regular capillaries?
What would happen if the vasa recta were a simple capillary?
How is this avoided? What occurs on the left side of the vasa recta as it descends into the medulla?
How does this affect plasma osmolality?
What is the viscosity here due to?
What happens in the vasa recta on the ascent to the cortex?
What does this enable?
- The vasa recta surround the Loop of Henle in juxtamedullary nephrons
- As with most capillary beds, they bring nutrients and O2 and remove waste
- It is different to simple capillaries in that it moves very slowly, becomes quite viscous at the hairpin bend
- If the vasa recta was a simple capillary that ran parallel to the Loop and exited in the medulla – the osmotic gradient generated by the counter current multiplier would dissipate
- E.g. H2O would exit vasa recta and solutes would be reabsorbed
- This is avoided because the vasa recta form parallel hairpin bends to the Loop of Henle
- On the left side: H2O will diffuse out and solutes will diffuse in as the vasa recta descends into the medulla
- The plasma osmolality increases, but not quite matching the medullary interstitium
- Viscosity here is due to lack of H2O, and build-up of solute as well as plasma proteins
- The reverse happens in the vasa recta on the ascent back to the cortex – water diffuses out of the vasa recta and solutes diffuse back in – reducing the osmolality
- This enables blood supply without washout of the osmotic gradient generated
When will a dilute urine be produced?
What does this result in?
Describe the 6 steps in producing a dilute urine?
What 2 things is the Hyperosmotic medullary interstitium generated by?
What is it maintained by?
- A dilute urine will be produced when we water replete a subject
- This results in No AVP (ADH) and Osmolality of medullary interstitium being ~500 mOsm/kg.
- 6 steps in producing a dilute urine:
1) Tubular fluid from PCT (300 mOsm/kg) enters thin descending limb
2) H2O is reabsorbed via AQP1 due to hyperosmotic medullary interstitium (concentrates the tubular fluid osmolality)
3) Urea is secreted into the tubules of the thin limbs of the LOH via UT-A2, which will increase tubular fluid osmolality
4) NaCl is actively transported in the TAL of the LOH via NKCC2. This forms the counter current multiplier mechanism which generates a hyperosmotic medullary interstitium. Tubular fluid becomes hypoosmotic due to the loss of NaCl.
5) No water is reabsorbed in the DCT, CCD or MCD but NaCl is further reabsorbed in these portions: NCC in the DCT and ENaC in the CD, which further dilutes the tubular fluid.
6) Urea reabsorbed from MCD via UT-A1 and UT-A3, further diluting the tubular fluid. Some urea recycles back into the Loop. Final osmolality of the urine ~60 mOsm/kg
- 2 things is the Hyperosmotic medullary interstitium generated by:
1) Counter current multiplier mechanism of NaCl reabsorption in the TAL
2) Urea reabsorption in the MCD Hyperosmotic medullary interstitium maintained by:
- It is maintained by counter current exchanger, preventing washout
When will a concentrated urine be produced?
What does this result in?
Describe the 6 steps in producing a concentrated urine?
What 2 things is the Hyperosmotic medullary interstitium generated by?
What is it maintained by?
- Concentrated urine can be produced when we water restrict a subject
- This results in a lot of AVP and Osmolality of medullary interstitium being ~1200 mOsm/kg.
- 6 steps in producing a concentrated urine:
1) Tubular fluid from PCT (300 mOsm/kg) enters thin descending limb
2) H2O is reabsorbed via AQP1 due to hyperosmotic medullary interstitium (concentrates the tubular fluid osmolality
3) Urea is secreted into the tubules of the thin limbs of the LOH via UT-A2, which will increase tubular fluid osmolality
4) NaCl is actively transported in the TAL of the LOH via NKCC2. This forms the counter current multiplier mechanism which generates a hyperosmotic medullary interstitium. Tubular fluid becomes hypoosmotic due to the loss of NaCl.
5) H2O is reabsorbed in the CCD & MCD – equilibrating tubular fluid to the medullary interstitium. Removal of water outweighs the NaCl that is reabsorbed in these portions: NCC in the DCT & ENaC in CD
6) Urea reabsorbed from MCD via UT-A1 and UT-A3, but water is also reabsorbed. Some urea recycles back into the Loop. Final osmolality of the urine ~1200 mOsm/kg
- 3 things the Hyperosmotic medullary interstitium is generated by:
1) Counter current multiplier mechanism of NaCl reabsorption in the TAL
2) Urea reabsorption in the MCD Hyperosmotic medullary interstitium maintained by:
- It is maintained by the counter current exchanger, preventing washout
