Renal Regulation Of Water And Acid Base Balance

Question 1

Osmosis

Answer 1

Flow of water from area of low solute conc to area of high solute conc across a semi-permeable membrane Osmolarity (Osm/L or mOsm/L) = conc x no. of dissociated particles

Question 2

Calculate the osmolarity for 100 mmol/L glucose and 100 mmol/L NaCl

Answer 2

• Osmolarity for glucose = 100 x 1 = 100 mOsm/L
• Osmolarity for NaCl = 100 x 2 = 200 mOsm/L → this is because NaCl’s dissociated particles is both Na+ and Cl-

Question 3

Describe the body’s fluid distribution in different compartments (in %)

Answer 3

60% of body weight is fluid

• 2/3 Intracellular fluid
• 1/3 extracellular fluid (ECF)
  
  • 1/4 of this is intravascular (plasma in bloodstream)
  • 3/4 of this is extravascular
    
    • 95% of this is interstitial fluid (that surrounds and bathes cells)
    • 5% of this is transcellular fluid (including cerebrospinal fluid, peritoneal fluid)- very important though

Question 4

What are ways of unregulated water loss? (4)

Answer 4

• Sweat
• Faeces
• Vomit
• Water evaporation from respiratory lining and skin

Question 5

What is the regulated way of losing water?

Answer 5

Renal regulation through urine production

It does this through positive and negative water balance

Question 6

Describe the steps for positive water balance

Answer 6

High water intake → increases ECF volume (that is the first place water goes when it enters body) → lowers Na+ conc → lowers osmolarity → kidney produces hypoosmotic urine to lose water → osmolarity of ECF normalises

Question 7

Describe the steps for negative water balance

Answer 7

Low water intake → lowers ECF volume → increases Na+ conc → increases osmolarity → leads to hyperosmotic urine production (compared to plasma) → osmolarity of ECF normalises

Question 8

What happens at PCT water-wise?

Answer 8

67% of water is reabsorbed at PCT

Question 9

What happens in the descending loop of Henle?

Answer 9

• Water passively reabsorbed
• NaCl isn’t reabsorbed

Question 10

What happens in the ascending loop of Henle?

Answer 10

• NaCl is reabsorbed passively in the thin ascending limb
• NaCl is also reabsorbed actively in the thick ascending limb
• Water can’t be reabsorbed

Question 11

What happens at the DCT and collecting duct?

Answer 11

• There’s a variable amount of water reabsorbed depending on body’s needs
• Action of ADH kicks in here to modulate aquaporin channels (open and closing them) to vary amount of water reabsorption

Question 12

• When it comes to water reabsorption from kidney, how and why is it done passively?

Answer 12

• Water is reabsorbed through the passive process of osmosis and requires a gradient
• This is done because body doesn’t want to spend too much energy absorbing water
• The medullary interstitium needs to be hyperosmotic for water reabsorption to occur from Loop of Henle and collecting duct

Question 13

Describe how the process of countercurrent multiplication works in steps

Answer 13

1) Filtrate arrives at loop of Henle at 300 mOsm/L which is isoosmotic with the plasma (300 mOsm/L too)

2) Active salt reabsorption occurs- in the thick ascending loop, salt is actively reabsorbed into interstitium so osmolarity in tubular filtrate of ascending loop decreases 300 → 200 and medullary interstitium osmolarity rises 300 → 400 because salt is being added

3) Passive water reabsorption occurs- since interstitium osmolarity is higher, water from descending loop moves into interstitium through osmosis to equilibrate the osmolarity- this causes descending loop osmolarity to increase 300 → 400

These 2 steps above basically repeat themselves over and over again now:

4) More filtrate arrives at descending loop (at 300 mOsm/L) and pushes rest of filtrate along loop which changes up the osmolarities along the loop

5) Active salt reabsorption occurs- salt gets reabsorbed from thick ascending loop which increases osmolarity of interstitium and osmolarity in ascending loop falls

6) Passive water reabsorption occurs- water flows out from descending limb into interstitium so descending loop osmolarity increases til its = to interstitium osmolarity

Gradient in medullary interstitium already developing from outer medulla to inner medulla

This process repeats again and again (hence multiplication process) to achieve a proper gradient down medulla

It’s called counter current because filtrate flows in opposite directions in ascending and descending loops of Henle

Question 14

• How does countercurrent multiplication help us?

Answer 14

helps water passively reabsorb into body without spending a lot of energy

Question 15

In collecting duct cells what side does the basolateral cell membrane face?

Answer 15

The side with the blood capillaries
Apical cell membrane faces the lumen of the collecting duct

Question 16

What is the vasa recta?

Answer 16

A series of blood capillaries that surround nephron mainly in medullary region

Question 17

What happens to urea after being filtered through Bowman’s capsule?

Answer 17

1) It travels through nephron and reaches collecting duct

2) Through UT-A1 and UT-A3 transporters the urea is transported out into medullary interstitium (conc of urea in interstitium can be as high as 600 mmol/L) where UTAQ is on the apical membrane and UTA3 in the basolateral

3) Urea in interstitium can now either:

• go into vasa recta through UT-B1 transporter which surrounds nephron so urea circulates medullary region
• go into descending limb of loop of Henle through UT-A2 transporter where it goes back through nephron and some exits collecting duct back into interstitium again (recycling)

Question 18

What is the purpose of the recycling of urea?

Answer 18

To increase interstitium osmolarity which:

• Allows urine concentration to occur- water moves from collecting duct into interstitium (cuz osmolarity in interstitium is higher)
• Urea excretion requires less water- this is because when filtrate reaches inner medullary collecting duct it equilibrates with urea in inner medullary interstitium (which could be as high as 600 mmol/L so conc of urea in collecting duct could also go up to as high as this)- this urea then requires less water to excrete

Both of these methods ultimately help us to conserve water in our body

Question 19

What does vasopressin do to this mechanism?

Answer 19

Helps boost UT-A1 and UT-A3 numbers to increase collecting duct’s permeability for urea to aid urea reabsorption

Question 20

Vasopressin

Answer 20

Protein hormone with length of 9 amino acid
Promotes water reabsorption from collecting duct,helps in urea reabsorption and sodium reabsorption

Question 21

Where is vasopressin produced

Answer 21

In hypothalamus by neurones in supraoptic and paraventricular nuclei

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Once produced it’s packaged into granules and sent to the posterior pituitary for storage

Question 22

How does plasma osmolarity affect vasopressin

Answer 22

• Increase in plasma osmolarity is detected by osmoreceptors in hypothalamus (are sensitive to even 2-3% change) this stimulates ADH production and release to open aquaporin channels in collecting duct to reabsorb water
• Decrease in plasma osmolarity inhibits ADH production and release to keep aquaporin channels closed because we have excess fluid in plasma which we want to lose

Question 23

What is plasma osmolarity in a healthy adult?

Answer 23

275-290 mOsm/kg H2O

Question 24

How does hypo and hypervolemia affect vasopressin

Answer 24

• Hypovolemia means low blood volume → decreases blood pressure → detected by baroreceptors → info transmitted to hypothalamus → body wants to conserve fluid so this stimulates ADH production and release to open aquaporins to reabsorb water
• Hypervolemia means high blood volume → increases blood pressure → detected by baroreceptors → info transmitted to hypothalamus → body wants to get rid of excess fluid so inhibits ADH release to keep aquaporins closed to lose water

Question 25

How much of a change in blood pressure is needed for baroreceptors to detect vasopressin

Answer 25

5-10%

Question 26

What other factors stimulate ADH production and release? (3)

Answer 26

- Nicotine - Nausea - Angiotensin II

Question 27

What other factors inhibit ADH production and release? (2)

Answer 27

- Ethanol - Atrial natriuretic peptide

Question 28

Describe how ADH works at the collecting duct

Answer 28

1) ADH binds to V2 receptor on basolateral membrane of principal cells of collecting duct 2) This triggers G-protein mediated signal cascade in cell 3) This activates protein kinase A 4) This increases secretion of aquaporin 2 channels in vesicle form which are inserted into apical cell membrane 5) Water then absorbed through aquaporin 2 into cell then through aquaporin 3 and 4 in basolateral cell membrane into blood vessel **Overall ADH up/downgrades both AQP2 (apical membrane) and AQP3 (basolateral membrane) numbers as required**

Question 29

What is diuresis?

Answer 29

Increased excretion of dilute urine Mechanism: 1) ADH amount is 0 or small 2) Blood filtered at Bowman’s capsule and filtrate enters nephron 3) Filtrate passes into PCT where 67% of water and 67% of NaCl are reabsorbed into body 4) Isoosmotic fluid reaches descending limb of loop of Henle where water passively moves into interstitium 5) Fluid enters ascending limb of loop of Henle where NaCl is reabsorbed into interstitium leaving hypoosmotic fluid 1) ADH amount is 0 or small 2) Blood filtered at Bowman’s capsule and filtrate enters nephron 3) Filtrate passes into PCT where 67% of water and 67% of NaCl are reabsorbed into body 4) Isoosmotic fluid reaches descending limb of loop of Henle where water passively moves into interstitium 5) Fluid enters ascending limb of loop of Henle where NaCl is reabsorbed into interstitium leaving hypoosmotic fluid 7) Hypoosmotic fluid enters collecting duct where more NaCl is reabsorbed - Through Na+ channels and Na+ K+ ATPase pump  8) When it reaches inner medullary region, some water is also reabsorbed since some aquaporins are always present and water moves via other pathways e.g. paracellularly between epithelial cells 9) This leaves the fluid even more hypoosmolar to create urine at 50 mOsm/L compared to plasma which is 300 mOsm/L

Question 30

- At a cellular level how is NaCl reabsorbed in thick ascending limb?

Answer 30

1) Na+ K+ ATPase pump pumps Na+ into blood creating low conc of Na+ in cell 2) Through Na+ K+ 2Cl- symporter, Na+ moves from region of high Na+ (in tubular fluid) to low Na+ in cell which releases energy which K+ and Cl- use to get transported through this symporter into the cell 3) Once in cell K+ and Cl- then exit cell into blood through K+ Cl- symporter

Question 31

At a cellular level how is NaCl reabsorbed in the DCT?

Answer 31

1) Through Na+ K+ ATPase pump, Na+ is pumped into blood 2) NaCl enters cell from tubular filtrate through Na+ Cl- symporter 3) KCl leaves cell into blood via K+ Cl- symporter

Question 32

At a cellular level how is Na+ reabsorbed in collecting duct?

Answer 32

Through Na+ channels and Na+ K+ ATPase pump

Question 33

What is antidiuresis?

Answer 33

Concentrated urine excreted in low volumes- could be due to dehydration or disease

Question 34

Describe the mechanism for anti diuresis

Answer 34

1) There is a high amount of ADH 2) Fluid filtered through Bowman’s then passes through PCT where 67% water and 67% NaCl is reabsorbed leaving isosmotic fluid 3) Water moves out of fluid in descending limb and NaCl moves out of fluid in ascending limb of loop of Henle leaving hypoosmolar fluid 4) In DCT then collecting duct NaCl is again actively reabsorbed 5) In DCT and collecting duct, AQP2 are present so water is reabsorbed 6) In collecting duct there is a gradient of osmolarity which increases as you go down it meaning more and more water is reabsorbed into interstitium from outer medullary to inner medullary regions 7) By the time urine leaves kidneys the osmolarity could be as high as 1200 mOsm/L and urine volume as low as 500ml per day

Question 35

What does ADH do in terms of Na+ reabsorption?

Answer 35

Supports it in: - Thick ascending limb- increased Na+ K+ 2Cl- symporters - DCT- increased Na+ Cl- symporters - Collecting duct- increased Na+ channels

Question 36

Central Diabetes Insipidus

Answer 36

- Cause? - Decreased/negligent production and release of ADH - Can be genetic or acquired due to e.g. infection or trauma - Clinical features? **(2)** - Polyuria- large urine volume - Polydipsia- thirst - Treatment? External ADH

Question 37

Nephrogenic Diabetes Insipidus

Answer 37

- Cause? Correct amount of ADH produced but something going wrong at collecting duct - Fewer/mutant AQP2 - Mutant V2 receptors - Clinical features? **(2)** - Polyuria - Polydipsia - Treatment? **(2)** - Thiazide diuretics- reduce filtration rate at Bowman’s capsule so less blood filtered so less urine produced - NSAIDs

Question 38

Symptom of inappropriate ADH secretion (SIADH)

Answer 38

- Cause? Increased production and release of ADH - Clinical features? **(3)** - Hyperosmolar urine - Hypervolemia - Hyponatremia - Treatment? Non peptide inhibitor of ADH receptor (conivaptan and tolvaptan)

Question 39

How are acids and bases added to our body?

Answer 39

Through diet and metabolism - A lot of base is excreted in faeces - There is however a net addition of metabolic acid to our fluid compartments (50-100 mEq/day) - Otherwise it’ll impact blood pH

Question 40

How is excess metabolic acid neutralised

Answer 40

- By different buffer systems, mainly by bicarbonate buffer system - This produces sodium salts and CO2

Question 41

How much bicarbonate do we have in ECF compartment?

Answer 41

350mEq or 24mEq/L If the body just continuously used bicarbonate to neutralise metabolic acids without replenishing it, the bicarbonate would run out in 4-7 days Kidneys make sure HCO3- is replenished by: - Helps with secretion and excretion H+ → there is a fine balance because if body secretes more H+ than metabolic acids coming in, there will be an alkalosis and if less H+ is secreted then acidosis will occur - Reabsorption of 100% of HCO3- - Production of new HCO3-  -  - What does this equation highlight? The bicarbonate ion buffer system is a unique buffer system which is managed by both lungs (through CO2) and kidneys (through HCO3-) - What does the Henderson-Hasselbalch equation help us study? - The role that PCO2 and conc of HCO3- plays on blood pH - It shows that if PCO2 rises in body, this increases H+ ion conc causing acidosis and if it falls it causes an acidosis - It also shows inverse relationship of H+ conc with HCO3- conc → if HCO3- rises it’ll cause alkalosis and if it falls it’ll cause an acidosis - What is an acid-base disorder due to changes in PCO2 called? Respiratory disorder - What is an acid-base disorder due to changes in HCO3- conc called? Metabolic disorder 

Question 42

What does the Henderson-Hasselbalch equation help us study?

Answer 42

- The role that PCO2 and conc of HCO3- plays on blood pH - It shows that if PCO2 rises in body, this increases H+ ion conc causing acidosis and if it falls it causes an alkalosis - It also shows inverse relationship of H+ conc with HCO3- conc → if HCO3- rises it’ll cause alkalosis and if it falls it’ll cause an acidosis

Question 43

What is an acid-base disorder due to changes in PCO2 called?

Answer 43

Respiratory disorder

Question 44

- What is an acid-base disorder due to changes in HCO3- conc called?

Answer 44

Metabolic disorder

Question 45

- How much HCO3- is reabsorbed in nephron at different areas? -

Answer 45

- 80% in PCT - 10% in loop of Henle - 6% in DCT - 4% in collecting duct

Question 46

- Describe how HCO3- is reabsorbed at PCT

Answer 46

1) CO2 enters cell from tubular fluid by diffusion 2) CO2 reacts with H2O in presence of carbonic anhydrase to make H+ and HCO3- 3) H+ can leave cell into tubular fluid through 2 methods: - Through Na+ H+ antiporter- using downward energy from Na+ travel into cell from tubular fluid, H+ moves into tubular fluid - Through H+ ATPase pump which pumps H+ ion 4) HCO3- from the reaction is reabsorbed from cell into blood through Na+ HCO3- symporter 5) The H+ that left the cell into tubular fluid then reacts with HCO3- in fluid to form H2CO3 which splits into H2O and CO2, the CO2 of which moves back into cell to start from step 1) with the main final step being the HCO3- leaving cell into blood

Question 47

Describe how HCO3- is reabsorbed at DCT and collecting ducta

Answer 47

Alpha intercalated cell causes HCO3- reabsorption and H+ secretion

Question 48

What does beta intercalated cell do?

Answer 48

HCO3- secretion and H+ reabsorption

Question 49

alpha intercalated cell:

Answer 49

1) H2O + CO2 leads to H+ and HCO3- 2) H+ moves into tubular fluid via H+ ATPase pump and H+ K+ ATPase where it combines with HCO3- to form H2CO3 which splits into H2O and CO2, the CO2 of which diffuses back into cell to do step 1) 3) HCO3- moves into blood via Cl- HCO3- antiporter

Question 50

At beta intercalated cell:

Answer 50

1) H2O + CO2 leads to H+ and HCO3- 2) Cl- HCO3- antiporter secretes HCO3- into tubular fluid (to excrete in the case of alkalosis in body due to excess HCO3-) 3) H+ is absorbed back into blood via H+ ATPase pump

Question 51

Describe how new HCO3- is produced at PCT

Answer 51

1) 1 glutamine molecules gives 2 NH4+ molecules and 1 divalent ion (A2-) which gives rise to 2 HCO3- 2) The 2 NH4+ is excreted into tubular fluid through 2 methods: - Through Na+ H+ antiporter (NH4+ substitutes in place of H+) - Turns into NH3 and moves into tubular fluid where it combines with a H+ to form NH4+ again 3) NH4+ then excreted from body leaving us with a net gain of 2 HCO3-

Question 52

- this stage, why do we not want the 2 ammonia ions to enter blood?

Answer 52

If it does, it will go to liver and be split into NH3 and H+, the H+ of which will require 1 HCO3- to neutralise it, which will nullify the effect of the 2 HCO3- we just produced from splitting the glutamine

Question 53

Describe how new HCO3- is produced at DCT and collecting duct

Answer 53

- In alpha intercalated cell, when H+ is secreted into tubular fluid, instead of being neutralised by a HCO3-, it’s neutralised by a non-bicarbonate buffer- a phosphate ion H+ + HPO42- → H2PO4- - By using a non-bicarbonate buffer, the HCO3- that is produced in the alpha intercalated cell and reabsorbed into blood is a net gain of HCO3-

Question 54

How is metabolic acidosis characterised?

Answer 54

Decrease in HCO3- conc leading to decrease in pH - What is the compensatory response? - Increased (hyper)ventilation which kicks in first → PCO2 goes down so H+ conc goes down - Increased HCO3- conc reabsorption and production to compensate for decrease in conc -

Question 55

How is metabolic alkalosis characterised?

Answer 55

Increased HCO3- conc leading to increased pH - What is the compensatory response? - Decreased (hypo)ventilation which kicks in first → PCO2 goes up so H+ conc goes up - Increased HCO3- conc excretion to compensate for increase in conc

Question 56

How is respiratory acidosis characterised?

Answer 56

Increased PCO2 leading to lower pH - How is this compensated? - Acute- increased CO2 enters cells where it reacts with H2O in presence of carbonic anhydrase to produce a H+ and a HCO3- and the H+ is neutralised by cellular proteins so there’s a net gain of HCO3- which is transported back into blood to help with increasing pH - Chronic- increased HCO3- reabsorption and production in kidney along with increased H+ and NH4+ ion excretion to help normalise pH

Question 57

How is respiratory alkalosis characterised

Answer 57

Decreased PCO2 leading to higher pH - How is this compensated? - Acute- shifting bicarbonate buffer reaction towards more carbonic acid production so less HCO3- produced - Chronic- decreased HCO3- reabsorption and production in kidney to normalise pH