Renal - regulation of water and electrolyte balance Flashcards
Summarise the distribution of total body water
60% of 70 kg = 42 L
ECF (14 L)
- plasma: 3
- Interstitium: 10
- transcellular: 1
ICF (28 L)
- Intracellular: 28
How can intracellular fluid, interstitial fluid and total body water be calculated?
Plasma
- agent cant cross endothelial membrane
- radio-labelled albumin
ECF
- agent can cross endothelium but not phospholipid bilayer
- thiosulphate
Total body water
- agent can cross both endothelial barrier and phospholipid bilayer
- Deuterated water (2H2O)
ICF and interstitial can be calculated from these values
The above is based on the formula:
n = C x V
How does osmolarity differ from molarity
Osmolarity is defined as the number of osmoles per litre of solution, where osmoles denotes the number of moles of particles that are able to exert an osmotic pressure.
Molarity is the number of moles of a particular solute dissolved per litre of solution; that is, the concentration
What is the formula for serum osmolarity
[Plasma] = 2[Na] + 2[K] + [glucose] + [urea]
How does osmolality differ from osmolarity.
Osmolality is the number of osmoles per kilogram of solvent
–> independent of temperature and weight of solute
Osmolarity is the number of osmoles per litre of solution
–> The volume of the solution changes with temperature and volume of solute
What is the osmolar gap? What does the presence of an osmolar gap indicate?
It is the difference between the measured osmolality and calculated osmolarity
Osmolar gap = osmolality - osmolarity
The osmolar gap indicates the presence of additional unmeasured osmotically active particles in the plasma that are NOT INCLUDED IN THE ESTIMATION OF PLASMA OSMOLARITY E.g. 1. Alcohol intoxication 2. Hypertryglyceridaemia 3. Methanol 4. Ethylene glycol
Why is 5% Dextrose infused instead of free water to rehydrate patients
If free water is infused, acute dop in venous blood tonicity occurs. The hypotonic solution causes red blood cells to swell and haemolyse. 5% dextrose is used instead as this solution has an osmolarity of 278 mOsmol/L which is close to plasma osmolarity of 285 - 298 mOsmol/L. Once the glucose is metabolized, free water has been infused but without the acute drop in osmolarity.
How is plasma osmolarity controlled
Feedback loop.
SENSOR:
Osmoresceptors in the hypothalamus.
- Extremely sensitive: 1% change detected
CONTROL CENTER:
Hypothalamus
- Normal set point is 285 - 298 mmol/L
EFFECTORS
Hypothalamus
1. Stimulates thirst
2. Reduce water excretion by the kidney –> ADH
What is ADH
Antidiuretic Hormone
Arginine Vasopressin
It is a nine amino acid peptide
Synthesis:
Hypothalamus PVN and SON (paraventricular and supraoptic nuclei)
Transfer:
To posterior pituitary where it is stored in granules
Secretion:
Controlled by hypothalamus in response to increased osmolarity
Apart from the insertion of aquaporins into the collecting duct, what other function does ADH have?
Peripheral vasoconstriction
–> normally circulating ADH has negligible influence on arteriolar tone.
However, in situations of hypovolaemic shock, the posterior lobe of the pituitary secretes large amounts of ADH. At high concentrations, ADH is a powerful vascoconstrictor and plays an important role in maintaining systemic blood pressure.
How does ADH act on the kidney
Basolateral membrane faces capillaries
Luminal membrane faces lumen
There are existing aquaporins 3 and 4 on the basolateral membrane so this side is already permeable to water.
Aquaporin 2 is inserted into the luminal membrane of the collecting duct cells in response to stimulation of V2 receptors by ADH. V2 –> cAMP –> aquaporin 2 insertion
Water then moves in, through the collecting duct cell, into the blood down its concentration gradient established by:
- High osmolarity of renal medulla (LOH countercurrent exchange mechanism)
- Urea cycling
How is the high osmolarity of the renal medulla generated
THIN DESCENDING LIMB LOH:
- permeable to water
- impermeable to ions and urea
THIN ASCENDING LIMB LOH
- impermeable to water
- Permeable to ions and urea
THICK ASCENDING LIMB
- Impermeable to water
- Permeable to ions and urea
- Secondary active transport: Luminal Na/K/2Cl- co transporters powered by basolateral Na/K ATPase
This establishes a high osmolarity in the renal medulla. which is maintained by the hairpin countercurrent arrangement of the associated vasa recta as the solutes are not washed away. The vasa recta descend with the ascending lop and ascend with the descending loop.
What is diabetes insipidus
CENTRAL DIABETES INSIPIDUS (E.g. intracranial disturbance –> hypothalamic dysfunction)
- ADH secretion failure
- large volume dilute urine
- hypernatraema
- elevated serum osmolarity
- low urine osmolarity
NEPHROGENIC DIABETES INSIPIDUS
- E.g. Lithium
- Collecting ducts fail to respond to ADH
- same clinical findings as above
What is SIADH
Syndrome of inappropriate ADH secretion
- excessive ADH from posterior pituitary or from an ectopic source (e.g. small cell lung carcinoma)
–> HYPONATRAEMA (and low plasma osmolarity)
Headache, nausea, confusion, seizures, coma
Sometimes with fluid overload
–> Inappropriately high urine osmolarity
Describe how urea is handled through the nephron
PCT
50% of filtered urea is reabsorbed
LOH
60% urea is secreted into the tubular lumen
110% of filtered urea is now present within the lumen at the DCT
Collecting duct (Inner medullary) 70% urea reabsorbed
Urine contains about 40% of filtered urea.
so essentially urea is reabsorbed (PCT), the secreted (LOH), then transported in the lumen to the inner medullary collecting duct where it is reabsorbed. The reabsorption of urea here contributes to the high inner medullary osmolarity necessary for water reabsorption.
Apart from aquaporin 2 insertion into the CD luminal membrane and vascoconstriction during shock, what other function does ADH have
It increases the insertion of Urea Transporter A1 (UT-A1) into the luminal membrane of the inner medullary collecting duct
Classify the mechanisms of control of sodium excretion
- Changes to GFR
- high plasma volume –> high GFR –> increases Na excretion
- low plasma volume –> low GFR –> reduced Na excretion - Changes to tubular Na reabsorption
Discuss the reabsorption of Na in the various regions of the nephron
PCT - 60%
- Basolateral Na/K ATPase
- ->
1. Passive diffusion Na (low intracellular Na)
2. Co-transport: SGLT
3. Counter-transport: Na+/H+
LOH (thick ascending) - 30%
- Na/K/2Cl co-transporter
DCT and collecting duct
- Aldosterone mediated Na reabsorption
1. Early DCT Na/Cl co-transporter (5%)
2. Late DCT and collecting duct (2%) - —–> PRINCIPLE cells: Na/K counter-transporter
- —–> INTERCALATED cells: Na/H counter-transporter
Summarise the physiological response to low plasma volume
ANP and BNP reduced (atrial stretch receptors)
‘Hypovolaemia hormones’ secreted
- Noradrenalin
- -> afferent and efferent VC –> reduced GFR –> reduced Na excretion - ADH increase
- -> Increased reabsorption H2O from collecting duct - Renin increase
- -> ANG II: PCT –> increases Na reabsorption
- -> Aldosterone: DCT –> increased Na reabsorption
Overall: Conservation of fluid through reduction of GFR and reduction in sodium excretion
What is the maximum possible concentration of urine. And what is the minimum daily urine output and why?
What is the volume of insensible fluid losses per day?
Therefore, what is the minimum daily intake of fluid required?
1200 mmol/L and equals the concentration of the interstitium in the inner renal medulla.
The kidney must excrete osmotically active waste products accounting for about 600 mOsmol/day
So, minimum daily urine out: V = n/c
600 mOsmol
____________
1200 mOsmol/L
= 500 mL/day
Insensible losses ± 500 ml/day
Minimum daily fluid intake is therefore 1000 mL
Classify diuretics and summarise their mechanism of action
Osmotic diretics e.g. mannitol
- Freely filtered into lumen with no reabsorption –> increase osmolarity of the filtrate –> reduced water reabsorption –> increased urine volume
CA inhibitors (acetazolamide) - Reduced HCO3- reabsorption --> increased HCO3- excretion in the urine
Loop diuretics (furosemide and bumetanide)
- Inhibit Na/K/2Cl co-transporter in thick ascending LOH
- reduced Na/K/Cl reabsorption PLUS disruption of counter-current mechanisms. Very effective and known as high-ceiling diuretics
Thiazide (HCTZ, bedroflumethiazide)
- Block Na/Cl co-transporter in the early DCT
Potassium sparing diuretics (spironolactone, amiloride, trimaterene)
- Spironolactone blocks aldosterone receptors in DCT / CD. Increased Na excretion and H+/K+ retention
- Amiloride blocks Na channels in the DCT and collecting duct (similar effects to spironolactone)
ADH is involved in regulating osmolarity and plasma volume. Which takes priority?
Small changes in osmolarity may lead to catastrophic brain swelling in the closed compartment of the cranium.
–> ADH response triggered with 2 - 3 % change in osmolarity
In contrast small changes in plasma volume are relatively well tolerated owing to the high compliance of the venous circulation, which acts as a blood reservoir
–> ADH response triggered with 7- 10% change in blood volume
HOWEVER, with large volume losses > 10% –> volume regulation takes priority owing to the possibility for tissue ischaemia.
What happens to ADH secretion when hypertonic saline is administered. What does this illustrate
Hypertonic saline will increase osmolarity (should increase ADH) and increase volume (should reduce ADH)
The response is an increase in ADH showing that ADH is regulation is more sensitive to osmolarity than volume.
Summarise the physiological response to a high plasma volume
- Stretch receptors: atria and pulmonary vessels –> respond to hypervolaemia by reducing their afferent output to the medulla –> reduced: noradrenalin, ADH and renin –> increased Na excreted in urine
- Dilution of plasma proteins and hence lower plasma oncotic pressure –> increased filtration fraction (Starling)
- ANP (atria) and BNP (ventricles)
- —-> 1. Afferent arteriolar vasodilatation with efferent arteriolar vasoconstriction –> increase GFR and hence Na excretion
- —-> 2. Relax glomerular mesangial cells –> increases surface area for filtration
- —-> 3. Block Na channels in DCT and CD
- —-> 4. Inhibits renin secretion by granular cells
- —-> 5. Inhibits aldosterone secretion from adrenal cortex
Summarise the effects of ANP and BNP
- Afferent VD + Efferent VC –> increased GFR and Na loss
- Mesangial cell relaxation –> increased SA for filtration –> increased GFR –> Na loss
- Block Na channels DCT + CD
- Inhibit renin release (granular cells)
- Inhibit aldosterone release (renal cortex)
Which substance is responsible for most of the intracellular osmotic pressure. Discuss proportions of this substance in the ECF and ICF
Potassium
98% in the ICF (150 mmol/L)
2 % in the ECF (3.5 - 5.5 mmol/L)
Why is it important that a concentration gradient of potassium from the ICF to the ECF is maintained
This gradient is responsible for maintaining the resting membrane potential of cells.
What is the minimum RDA water and electrolytes:
H2O – Na+ – K+ – Ca2+ – Mg2+ – PO4 –
H2O – 30 mL/kg Na+ – 2mmol/kg K+ – 1mmol/kg Ca2+ – 0.1 mmol/kg Mg2+ – 0.1 mmol/kg PO4 – 0.1 mmolkg
LITFL
How does the body deal with excessive potassium ingestion in the diet
Insulin stimulates basolateral Na/K ATPase whcih increases cellular K uptake reducing plasma levels
What are the mechanisms for potassium shifts
- Insulin –> Stimulates basolateral Na/K ATPase
- Alpha adrenoreceptor –> triggers K release from cells (ECF K triggers glycogenolysis + vasodilation in active muscle)
- Beta adrenoreceptor –> Stimulates basolateral Na/K ATPase
- Extracellular pH –> Excess H+ (acidosis) buffered by uptake into cells
- electroneutrality maintained by pushing K out
- or intracellular acidosis impaire Na/K ATPase less K moved in.
Reverse occurs in alkalosis.
Describe renal handling of potassium
Filtration: Freely filtered
PCT and LOH:
- Almost all K is reabsorbed in PCT and LOH (Na/K/2Cl)
- this occurs irrespective of whether body K is high or low
DCT and CD
- When plasma K is low:
- —–> Additional K is absorbed in the DCT (H+/K+ ATPase). 99% reabsorbed.
- When K + is high
- —-> Adrenal cortex directly stimulated to release aldosterone
Overall:
In low K –> 99% of K can be reabsorbed
In high K –> 80% of filtered potassium can be excreted
What is the mechanism of membrane stabilization when Calcium is given during hyperkalaemia
High K outside cell –> Less gradient for movement of K+ leaking out –> More positive charge remains in cell (vs outside cell) –> More depolarized membrane which is closer to membrane potential) –> cells are more excitable –> dysrhythmogenic.
Reverse is true for hypokalaemia
Ca+ ions bind to the outer surface of the membrane. This creates a local high density of positive charge outside the cell, hence creating a relatively more negative intracellular voltage.
What are the classical ECG findings in hypokalaemia
Think hyperpolarization of RMP
Think reduced excitability
Prolonged PR
ST depression
Inverted/flattened T waves
U waves
