Renal Regulation of Water and Acid-Base Balance Flashcards
What is osmotic pressure?
What is it proportional to?
The side pulling the particles
It is proportional to the no. of solute particles
What is osmolarity and it’s formula?
Osmolarity = Concentration x No. of dissociated particles
= Osm/L OR mOsm/L (units for osmolarity)
Is osmolarity always the same as osmotic pressure?
No, because osmolarity is also dependent on number of dissociated particles
Calculate the osmolarity for 100 mmol/L glucose and 100mmol/L NaCl?
Osmolarity for glucose = 100 x 1 = 100 mOsm/L
Osmolarity for NaCl = 100 x 2 = 200 mOsm/L
What is the total body fluid volume?
Where are they found int he body?
60% of body weight
2/3 of fluid sits intracellularly
1/3 of fluid sits in the extracellular fluid (ECF)
Of the ECF, 1/4 is plasma (intravascular) and 3/4 is extravascular
Of the extravascular fluid, 95% is interstitial fluid and 5% is transcellular fluid
Give examples of trans-cellular fluid?
CSF
Periotoneal fluid
What are the unregulated forms of water loss?
What is regulated water loss?
Unregulated = sweat, faeces, vomit, water evaporation from respiratory lining and skin
Regulated = renal regulation - urine production
In the body, what is positive water balance VS negative water balance?
Positive = having drunk lots of water (so lots of water within the body)
Negative = thirsty (need to drink more water)
How do your kidneys normalise a positive water balance VS a negative water balance?
Positive water balance = High water intake enters EC compartment ECF volume increases Sodium conc decreases Osmolarity decreases Hypo-osmotic urine production Osmolarity normalises
Negative water balance = Low water intake Low ECF volume High sodium conc Osmolarity increases Hyper-osmotic urine production Osmolarity normalises
How does water reabsorption occur in the nephrons?
In the PCT = 67% (2/3) water reabsorbed (as 67% of salt is reabsorbed)
Water is not re-absorbed in the ascending limb of the loop of Henle (but salt is)
Water is re-absorbed in descending limb of the loop of Henle (but no salt is)
DCT and CD = variable amount of water is reabsorbed depending on vasopressin / ADH
Why is the loop of Henle designed the way it is?
To make water reabsorption passive
As active reabsorption of water = energy wasting
Actively pumping out salt to change water osmolalities = passive reabsorption of water
The medullary interstitium needs to be hyperosmotic for water reabsorption to occur from the Loop of Henle and CD
What is the countercurrent multiplication system of the loop of Henle?
What is the osmolarity of the interstitial fluid at the top of the loop of Henle VS the bottom?
Filtrate arrives at loop of henle at osmolarity equal to plasma
Salt reabsorbed by being actively pumped out of ascending loop of henle into interstitual fluid
Osmolarity of interstitial fluid = increased
Osmotic pressure gradient from loop of Henle to interstitial fluid established
Water passively flows into interstitial from thin descending
Fresh filtrate arrives - process repeats itself
300 mOsm/L at top
1200 mOsm/L at bottom
How does urea contribute to water reabsorption?
What is this process called?
In the CD, the apical membrane faces the CD and the basolateral membrane faces the interstitial fluid
Filtrate arrives at collecting duct where there are two urea transporters, one on basolateral and one on apical membrane
The 2 urea transporters = UTA-1 and UTA-3
As urea is pumped out, it reaches the medullary interstitum and increases its osmolarity
Can be reabsorbed in the vasa recta (via UT-B1) and the thin descending limb of the loop of Henle via (UT-A2)
Urea keeps being recycled
Urea helps reabsorption of water in the descending limb and CD
This process is called urea recycling
Why recycle urea?
Increasing interstitium osmolarity = helps water reabsorption
Recycling the urea = urine concentration occurs in the CD so urea excretion requires less water
How does vasopressin affect urea?
Increases permeability of CD to urea by boosting UT-A1 and UT-A3
Leads to greater water reabsorption
Where does IV fluid infusion travel to first?
First enters ECF - whether orally or IV
After some time, it equilibrates with the ICF compartment
What is vasopressin / ADH (anti-dieuretic hormone)?
Where is it produced, stored and released?
9 amino acids long
Promotes water reaborption from CD
Produced in hypothalamus in the supraoptic neurons and paraventricular nuclei)
Stored in the posterior pituitary
What affects ADH production and release?
What detects plasma osmomlarity
Stimulates ADH production and release =
Increased plasma osmolarity
Hypovolemia
Decreased BP
Inhibits ADH production and release =
Decreased plasma osmolarity
Hypervolemia
Increased BP
Plasma osmolarity is detected by osmoreceptors
What inhibits ADH production?
Alcohol e.g. ethanol reduces ADH production = increased water loss = feeling dehydrated
ANP
What is the mechanism of ADH?
ADH arrives via blood vessel to V2 receptor on the epithelial cells of the CD
Binds to V2 receptor = G-protein mediated signalling cascade activates cAMP, cAMP activates protein kinase A
Increase in PKA stimulates an intracellular cascade which promotes secretion, movement + insertion of aquaporin 2 into the apical membrane of collecting duct (on tubular side) so water moves in from the urine (in lumen) to inside the cell
Water flows along concentration gradient out of the cell and into the plasma through aquaporin-3/ 4 channels on basolateral side
This process promotes reabsorption of water from collecting duct = lower volume more conc urine
ADH can up/downgrade number of AQP2 (on apical membrane) & AQP3 (on basolateral membrane) as required
What happens in the nephrons when ADH is very low?
PCT = 67% water and 67% salt reabsorbed
In DCT = hypoosmotic
Small amount of ADH = absence of aquaporin-2 (AQP2) channels on the CD = less water reabsorbed in the CD
Urine more dilute
How is NaCl reaborbed in the thin ascending limb?
Top of ascending limb: Na+ and Cl- actively pumped out of tubular fluid into medulla, but this bit is impermeable to water, water stays inside tubule. Creates low water potential in medulla/ high osmolarity
Na+/K+/ATPase on basolateral: pumps Na+ into interstitial fluid to be reabsorbed Na+/K+/ 2Cl- symporter on apical side: Na+, Cl-, K+ enter using Na+ gradient K+/Cl- symporter on basolateral: takes Cl- into interstitial fluid using K+ gradient
Low Na+ and Cl- inside cell:
Net movement of Na+ and Cl- out of tubular fluid so hypoosmotic fluid leaves loop of Henle
What happens during diuresis?
Na+/K+ ATPase on basolateral: pumps Na+ into interstitial fluid (low Na+ inside cell this allows:)
Cl- to be reabsorbed from tubular fluid by Na+/Cl- symporter on apical membrane
Impermeable to water so water can’t flow in with the ions
Then K+/Cl- symporter on BL carry K+ and Cl- into blood
Low ADH so AQP2 not present = water cannot leave DCT
Hypo-osmotic fluid enters collecting duct
Dilute urine
Why is some water reabsorbed in diuresis?
There is still some aquaporin (AQP) function
How does ADH support Na+ reabsorption in the kidney?
Thick ascending limb: increased Na+ - K+ - 2Cl- symporter
Distal convoluted tubule: increased Na+ - Cl- symporter
Collecting duct: increased Na+ channel
What occurs in anti-diuresis?
Concentrated urine in low volume excretion
If ADH High, it boosts Na+ reabsorption by increasing:
↑Na+/ K+/2Cl- symporter (Thick ascending limb BL membrane) ↑Na+/Cl- symporter (Distal convoluted tubule BL membrane) ↑Na+ channel (Collecting duct BL membrane)
So more Na+ enters cells from tubular fluid to be transported back into blood, so increase in Na+ reabsorption = increased water reabsorption at these places
ADH lso increases number of apical AQP2 in distal DCT and collecting ducts:
- As water passes through CD, a lot of water is reabsorbed into blood from tubular fluid (high gradient in medulla) producing hyperosmolar urine
More water reabsorbed in the medullary gradient tract = concentrated and low volume urine produced
What are some ADH-related clinical disorders?
Central diabetes insipidus
Syndrome of inappropriate ADH secretion
Nephrogenic diabetes insipidus
What is central diabetes insipidus? What is it caused by?
Genetic
Acquired - trauma, infection
Affects hypothalamus - caused by decreased / negligent production and release of ADH
Thirst triggered
What are the clinical features of central diabetes insipidus?
Polyuria
Polydipsia
What are the treatment options for central diabetes insipidus?
External ADH
What is Syndrome of inappropritate ADH secretion (SIADH)?
Increased production and release of ADH
Increased water retention = blood eventually becomes hypo-osmotic
What are the clinical features of SIADH?
Hyperosmolar urine
Hypervolemia
Hyponatremia
What are the treatment options for SIADH?
Non-peptide inhibitor of ADH receptor
conivaptan & tolvaptan
What is nephrogenic diabetes Insipidus?
Correct amount of ADH is being released, issue with CD
E.g. less / mutant AQP2 OR mutant V2 receptors
What are the clinical features of diabetes Insipidus?
Polyuria
Polydipsia
What are the treatment options for diabetes Insipidus?
Thiazide diuretics + NSAIDs
Reduce rate of filtration = less volume of blood being filtered = less water loss in the urine
What affects acid-base balance?
Diet and metabolism constantly adds acid and base to the blood
Which is added more, acid or base?
Base excretion in faeces leads to net increase of acid in blood (due to net addition of metabolic acid)
How is net acid increase controlled by the body?
Metabolic acid neutralisation using HCO3-
How much bicarbonate HCO3- is added each day? How?
A lot
Role of the kidneys:
Secretion and excretion of H+
Reabsorption of bicarbonate (almost 100% reabsorbed)
Production of new HCO3- = CO2 required for this so buffer system is managed by kidneys and lungs
How are metabolic acids (e.g. H2SO4 or HCl) neutralised?
H2SO4 + 2HCO3- —-> SO4 2- + 2CO2 + 2H2O
HCl + HCO3- —-> Cl- + CO2 + H2O
What is the ECF conc of bicarbonate (HCO3-)?
ECF [HCO3-] = ~350mEq
How is carbonic acid produced?
Carbonation of H2O (water)
Uses carbonic anhydrase
To produce H2CO3 (Carbonic acid)
CO2 + H2O H2CO3 H+ + HCO3-
What is the Henderson-Hasselbalch equation?
Describes the relationship between blood pH and the components of the H2CO3 buffering system
When CO2 conc. increases, H+ (pH) also increases, and vice versa
When HCO3- increases, H+ (pH) decreases, and vice versa
pH = pH + log(HCO3- / proportion of PCO2)
[H+] = (24 x PCO2) / [HCO3-]
Causes of acid base disorders?
PCO2 imbalance = respiratory
HCO3- imbalance = metabolic
PCT revision - How are bicarbonate ions reabsorbed?
80% of Bicarbonate is reabsorbed in PCT:
In tubular fluid H+ and HCO3- converted to CO2 and H2O
CO2 enters cell by diffusion and carbonic anhydrase converts CO2+H2O = H2CO3 = to HCO3- and H+ in PCT cells
Na+/K+/ATPase on basolateral membrane: pumps Na+ into interstitial fluid (low Na+ inside cell this allows:)
- HCO3- leaves cell by Na+/HCO3- symporter (on BL using Na+ gradient from pump) and is reabsorbed into blood
- H+ goes into tubular fluid by Na+/ H+ antiporter (using Na+ gradient) on apical side to go to urine OR it uses H+ ATPase Pump to pump H+ ions back into the tubular fluid
All of this allows bicarbonate in tubular fluid to enter blood
How are bicarbonate ions reabsorbed in the DCT and CD?
alpha-intercalated cell
beta-intercalated cell
What do alpha intercalated cells do? How is this achieved?
What do beta intercalated cells do? How is this achieved?
Alpha = secrete H+ into tubular fluid by pumping them across the apical surface into the lumen of the nephron and allow HCO3- reabsorption
Achieved by:
1. Have a H+ ATPase on apical membrane which uses ATP to pump hydrogen into the tubule against its concentration gradient and a H+/K+ ATPase that pumps H+ out and K+ in
- Cl-/HCO3- antiporter on BL allows HCO3- to be reabsorbed using Cl- gradient
Beta = promote HCO3- secretion & H+ reabsorption
Achieved by:
1. H+ ATPase pump on BL which pumps H+ out to be reabsorbed into blood
- Cl-/HCO3- antiporter on BL which pumps HCO3- back into the tubular fluid
What are the alpha and beta intercalated cells important for?
Alpha = important when in state of acidosis, and the body wants to lose excess H+
Beta = important when we are in a state of alkalosis and the body wants to lose extra HCO3- ions in urine
Are alpha or beta intercalated cells more important?
Alpha more important as you want to lose the H+ ions quickly - especially because there is usually a net increase in metabolic acid due to loss of bicarbonate in the faeces
Why are new bicarbonate ions formed?
To compensate for body’s excess production of acid
How do the kidneys produce more bicarbonate ions?
2 methods:
Ammioniogenesis (in PCT)
In DCT and CD
What is the process of ammoniogenesis to produce more bicarb in the PCT?
In PCT - kidneys must excrete ammonia ions
Glutamine releases 2 ammonia ions and an iminium ion (A2-):
A2- gives rise to 2 molecules of HCO3- which are reabsorbed into blood The 2 NH4+ ions need to be excreted from body or else they would be converted into urea and H+ by liver and this H+ would have to be neutralised by HCO3- which would lead to no net increase of HCO3- ions. NH4 splits into NH3 and H+ H+ transported to tubular fluid using Na+/H+ antiporter and diffusion in the form of NH3 gas. Once this gas reaches tubular fluid, it is protonated and NH4+ is excreted
How does the kidney produce more bicarb in the DCT and CD?
Carbonic anhydrase inside the cell produces H+ and HCO3- inside the cell and the proton is pumped out into the tubular fluid like before
Usually the H+ ion is neutralised by HCO3- so there would be no net gain of HCO3- but here the H+ are being neutralized by 𝐇𝐏𝐎𝟒 𝟐- (a urinary buffer that is NOT HCO3-) and H2PO4- is excreted out.
So the HCO3- ion produced by carbonic anhydrase is considered a new bicarbonate ion because its not being used up to neutralise H+
What are the 4 different acid-base imbalance disorders?
How are they each characteristed?
Metabolic acidosis = decreased [HCO3-] decreased pH
Metabolic alkalosis = increased [HCO3-] increased pH
Respiratory acidosis = increased PCO2 decreased pH
Respiratory alkalosis = decreased PCO2 increased pH
How are the 4 acid-base imbalance disorders compensated by the body?
Metabolic acidosis = hyperventilation = CO2 decreases (respiratory alkalosis), which decreases H+ ions and increases pH and increased [HCO3-] reabsorption and production in kidneys
Metabolic alkalosis = hypoventilation = CO2 increases (respiratory acidosis), which increases H+ ions this decreases pH and increased [HCO3-] excretion in kidneys
Respiratory acidosis =
Acute : intracellular buffering (increased CO2 is hydrated and converted to H+ and HCO3- by carbonic anhydrase and the H+ ion is taken care of by proteins and HCO3- transported to blood (to balance out decreased pH)
Chronic : increased [HCO3-] reabsorption and production in kidneys
Respiratory alkalosis =
Acute : intracellular buffering more CO2 is made inside cells from H+ and HCO3-
Chronic : decreased [HCO3-] reabsorption and production in kidneys
What are the normal blood pH, [HCO3-] and pCO2 values?
Blood pH = 7.4
[HCO3-] = 24 Eq/L
PCO2 = 40mmHg
