1B renal regulation of water and acid-base balance Flashcards
Define osmosis
Flow of water from area of low solute conc to area of high solute conc across a semi-permeable membrane
What is the driving force for osmosis?
Osmotic (aka oncotic) pressure which depends upon number (not size) of solute particles
How do we calculate osmolarity?
Osmolarity (Osm/L or mOsm/L) = conc x no. of dissociated particles
Calculate the osmolarity for 100 mmol/L glucose and 100 mmol/L NaCl
- 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-
How much of body weight is fluid?
60%
Describe the body’s fluid distribution in different compartments (in %)
- 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
What are ways of unregulated water loss?
- Sweat
- Faeces
- Vomit
- Water evaporation from respiratory lining and skin
What is the regulated way of losing water?
Renal regulation through urine production
It does this through positive and negative water balance
Describe the steps for positive water balance
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
Describe the steps for negative water balance
Low water intake → lowers ECF volume → increases Na+ conc → increases osmolarity → leads to hyperosmotic urine production (compared to plasma) → osmolarity of ECF normalises
What happens at PCT water-wise?
67% of water is reabsorbed at PCT
(facilitated by sodium absorption)
What happens in the descending loop of Henle?
- Water passively reabsorbed
- NaCl isn’t reabsorbed
What happens in the ascending loop of Henle?
- NaCl is reabsorbed passively in the thin ascending limb
- NaCl is also reabsorbed actively in the thick ascending limb
- Water can’t be reabsorbed
What happens at the DCT and collecting duct?
- 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
When it comes to water reabsorption from kidney, how and why is it done passively?
- 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
Describe how the process of countercurrent multiplication works in steps
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
How does countercurrent multiplication help us?
It helps water passively reabsorb into body without spending a lot of energy
In collecting duct cells what side does the basolateral cell membrane face?
The side with the blood capillaries
What side does the apical cell membrane face?
The lumen of the collecting duct (the inside of the tube)
What is the vasa recta?
A series of blood capillaries that surround nephron mainly in medullary region
What happens to urea after being filtered through Bowman’s capsule?
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)
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)
What is the purpose of the recycling of urea?
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
What does vasopressin do to urea filtration at the Bowman’s capsule?
Helps boost UT-A1 and UT-A3 numbers to increase collecting duct’s permeability for urea to aid urea reabsorption
What is Vasopressin?
Protein hormone with length of 9 amino acids
What is the main function of vasopressin?
Promote water reabsorption from collecting duct
What functions other than water reabsorption does vasopressin have?
- Helps in urea reabsorption
- Helps in sodium reabsorption
Where is vasopressin produced?
In hypothalamus by neurones in supraoptic and paraventricular nuclei
Where is vasopressin stored?
Once produced it’s packaged into granules and sent to posterior pituitary for storage
How does plasma osmolarity affect ADH production and release?
- 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
What is plasma osmolarity in a healthy adult?
275-290 mOsm/kg H2O
How does hypovolemia affect ADH production and release?
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
How does hypervolemia affect ADH production and release?
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
How much of a change in blood pressure is needed for baroreceptors to detect it?
5-10%
What factors other than plasma osmolarity and hypo/hypervolemia stimulate ADH production and release?
- Nicotine
- Nausea
- Angiotensin II
What factors other than plasma osmolarity and hypo/hypervolemia inhibit ADH production and release?
- Ethanol
- Atrial natriuretic peptide
Describe how ADH works at the collecting duct
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
What is diuresis?
Increased excretion of dilute urine
Describe the mechanism for diuresis occurring in the nephron
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
6) This hypoosmotic fluid enters DCT where AQP2 channels are absent since there’s negligible ADH, however NaCl is actively reabsorbed again- this makes the fluid even more hypoosmotic
7) Hypoosmotic fluid enters collecting duct where more NaCl is reabsorbed
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
At a cellular level how is NaCl reabsorbed in thick ascending limb?
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
At a cellular level how is NaCl reabsorbed in the DCT?
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
At a cellular level how is Na+ reabsorbed in collecting duct?
Through Na+ channels and Na+ K+ ATPase pump
What is antidiuresis?
Concentrated urine excreted in low volumes- could be due to dehydration or disease
Describe the mechanism for antidiuresis in the nephron
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
What does ADH do in terms of Na+ reabsorption (specific transporters)?
Supports it in:
- Thick ascending limb- increased Na+ K+ 2Cl- symporters
- DCT- increased Na+ Cl- symporters
- Collecting duct- increased Na+ channels
List some ADH related clinical disorders
- AVP deficiency
- AVP resistance
- Symptom of inappropriate ADH secretion (SIADH)
What are the causes of AVP deficiency?
- Decreased/negligent production and release of ADH
- Can be genetic or acquired due to e.g. infection or trauma
What are the clinical features of AVP deficiency?
- Polyuria- large urine volume
- Polydipsia- thirst
What is the treatment for AVP deficiency?
External ADH
What is the cause for AVP resistance?
Correct amount of ADH produced but something going wrong at collecting duct
- Fewer/mutant AQP2
- Mutant V2 receptors
What are the clinical features for AVP resistance?
- Polyuria
- Polydipsia
What treatments are given for APV resistance?
- Thiazide diuretics- reduce filtration rate at Bowman’s capsule so less blood filtered so less urine produced
- NSAIDs
What is the cause of SIADH?
Increased production and release of ADH
What are the clinical features of SIADH?
- Hyperosmolar urine
- Hypervolemia
- Hyponatremia
What treatment is given for SIADH?
Non peptide inhibitor of ADH receptor (conivaptan and tolvaptan)
How are acids and bases added to our body?
Through our diet and metabolism
What happens to the acids and bases added in our 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)
Why is it important to neutralise excess metabolic acid?
Otherwise it’ll impact blood pH
How is excess metabolic acid neutralised?
- By different buffer systems, mainly by bicarbonate buffer system
- This produces sodium salts and CO2
How much bicarbonate do we have in ECF compartment?
350mEq or 24mEq/L
Why is bicarbonate in the ECF compartment important?
If the body just continuously used bicarbonate to neutralise metabolic acids without replenishing it, the bicarbonate would run out in 4-7 days
How do kidneys come in regulating HCO3-?
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
- If less H+ is secreted then acidosis will occur
- Reabsorption of 100% of HCO3-
- Production of new HCO3-
What is the equation important in acid-base balancing?
What does the equation in acid-base balancing 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
How much HCO3- is reabsorbed in nephron at different areas?
- 80% in PCT
- 10% in loop of Henle
- 6% in DCT
- 4% in collecting duct
Describe how HCO3- is reabsorbed at PCT
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
Describe how HCO3- is reabsorbed at ascending limb of loop of Henle
Very similar to PCT
Describe how HCO3- is reabsorbed at DCT and collecting duct
-
Alpha intercalated cell
- HCO3- reabsorption and H+ secretion
-
Beta intercalated cell
- HCO3- secretion and H+ reabsorption
What happens at alpha intercalated cells?
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
What happens at beta intercalated cells?
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
Describe how new HCO3- is produced at PCT
1) 1 glutamine molecule gives:
- 2 NH4+ molecules
- 1 divalent ion (A2-) which gives rise to 2 HCO3-
2) The 2 NH4+ are 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-
Why do we not want the two ammonia ions to enter blood?
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
Describe how new HCO3- is produced at DCT and collecting duct
- 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-
How is metabolic acidosis characterised?
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
How is metabolic alkalosis characterised?
Increased HCO3- conc leading to increased pH
What is the compensatory response for metabolic alkalosis?
- 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
How is respiratory acidosis characterised?
Increased PCO2 leading to lower pH
How is respiratory acidosis 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
How is respiratory alkalosis characterised?
Decreased PCO2 leading to higher pH
How is respiratory alkalosis 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
