RENAL Control & Abnormalities of Body Water

Question 1

60-40-20 rule

water in L for 70kg man?

what are the different compartments?

Answer 1

We are about 60% water by weight, that body water is divided between what is inside the cells intracellular which is 40% and extracellular which is 20%.

The extracellular compartment is divided between what is in the blood (the plasma) and what the interstitial volume.

For a 70kg male, he would be 60% water by weight so his total body water would be 42L. Of this, of this 28L would be intracellular and about 14L extracellular.

The balance of water between the two, it is essentially osmosis that dictates this.

The EC compartment can be divided into two sub-compartments:
• Plasma
• Interstitial volume

Question 2

Where is the majority of the ecf?

clinical significance of this? what is this representative of?

Answer 2

Of the extracellular fluid volume, the majority of it will be in the interstitial compartment and less than 10% will be in the circulation.

This has clinical significance because the only compartment we have easy access to intravenously is the plasma volume, so this is representative of what is going on in the rest of the body in terms of composition of fluids.

Question 3

Volume regulation

Answer 3

maintain adequate ECFV to support plasma volume

Question 4

Osmoregulation

Answer 4

maintain osmotic equilibrium between ICFV and ECFV

Question 5

Barriers that separate the different compartments
barrier for intra and extraceullar? its permeability?
Barrier between plasma and interstitial fluid? permeability?

Answer 5

The barriers that separate the compartments are very important, the barrier separating the intracellular and extracellular compartment is the cell membrane.

The cell membrane is essentially impermeable to solutes and electrolytes, unless there are special channels for them.

The barrier between the plasma and interstitial compartment is very different, it is the capillary wall/endothelial cells which is quite permeable to solutes with the exception of plasma proteins.

For this reason, the composition of a plasma sample will be very similar to that of the interstitial volume, but the intracellular will be different.

Question 6

Dominant cations in the different compartments

Answer 6

K+ is the dominant cation intracellularly while Na+ extracellularly

Question 7

There are two ways of changing concentration,

Answer 7

one is change the volume of water or to change the amount of solute.

• If you have a beaker of water containing 140mM of Na+ and it is dissolved in 1L of water, so by definition we have a concentration of 140mM/L of Na+.
• If we added pure water, we would still have 140mM of Na+, but the volume has increased so the concentration of Na+ will decrease.
• If we lose water and Na+ remains the same, then concentration will increase.

Question 8

what is Osmolality?
How is it calculated?

osmolality vs osmolarity?

Answer 8

Osmolality relates to the number of particles per unit volume of solution, its calculation is very simple, by simply adding the individual concentrations of particles in the solution up:

• Osmolality is particles per Kg of solution
• Osmolarity is particles per L of solution

The difference is actually not hugely important, between the two it only results in about 2% difference. It is important for high accuracy, but conceptually they can be used interchangeably.

Question 9

what is the principal cation in ECFV?
How do you calculate plasma osmallity?
what is normal value for this?

Answer 9

Na+ is the principle cation in the ECFV, at around 140mmol/L.
-> Plasma osmolality in mOsmkg-1 can be estimated quite easily by doing
o 2[Na+] + 2[K+] + [glucose] + [urea]

We double the sodium and potassium because they are cations, so by definition they MUST have corresponding anions.
Normal plasma osmolality is around 290mOsmkg-1

Question 10

Plasma [Na] and osmolality
Why is changes in osmolality important to be controlled?
What is hyponatremia? effects?
What is hyperantremia? effects?
effects of abnormal water balance? (5)
What controls Na+? what does control of Na+ do to the body?
what controls body water? What does control of water do to the body?

How is volume regulation done?
how is osmoregulation done?

Answer 10

Changes in osmolality are important because osmolality has to be equalised over the body, so large shifts in osmolality in the ECF result in shifts of fluid between the compartments.

So, if ECFV osmolality is low due to hyponatremia, water will move into the ICFV, brain cells can swell.

If ECFV osmolality is high due to hypernatremia, then water will leave the ICFV and brain cells will shrink.

There will be serious neurological consequences of abnormal water balance, including
o	Behavioral disturbances
o	Confusion
o	Headache
o	Convulsions
o	Coma

1. Na+ is controlled by RAAS -> control of body Na+ is volume regulation
2. Body water is controlled by the ADH system -> control of body water is osmoregulation

Volume regulation is done by Na+ which is very important for BP, osmoregulation is done by controlling water excretion

Question 11

Total Body Water Balance
How do we intake water?
lose water?
effect of changing water balance?

Answer 11

Balance = Input – Output

We intake water via drink, food and metabolism, amounting to about 2L/day and we also lose water from the gut, insensible loss (from lungs and skin) and via renal excretion. This keeps our volume of water relatively constant.

Any changes in water balance will lead to changes in body fluid osmolality and hence shifting of water between IC and ECF.

We have a negative feedback control of water balance

Question 12

Physiological Response to Water Restriction
effect of no intake and loss of water?
what senses this? effect? effect on urine?

Answer 12

So here a person loses water, via sweating and breathing and there is no water intake.

In the plasma we see that Na+ concentration rises (because the same amount of Na+ is dissolved in a reduced volume of EC water), hence osmolality will rise and therefore this will be sensed by osmoreceptors in the hypothalamus leading to increased release of ADH from pituitary gland.

This increased ADH will result in a decreased urine volume and therefore increased urine osmolality. The reabsorption of water will aim to decrease plasma osmolality.

Question 13

Physiological Response to Increased Water Intake
effect of increase of water intake?
what senses this? effect on body? effect on urine?

Answer 13

If water intake increases, for example increased water absorption through the GI tract being most likely.

Plasma Na+ concentration will FALL, because the same amount of Na+ is dissolved in increased EC water. Hence osmolality will fall and there will be decreased release of ADH

This will result in an increased urine volume and this will have a lower osmolality.

Question 14

ADH (vasopressin)
What does it do? what does it regulate? What is the concentration of urine excretion in relation to?
Where is ADH synthesised? where is it packaged? where does it go next and where is it secreted from?

Answer 14

It is the main osmoregulation hormone.
o Regulates plasma osmolality primarily by controlling water excretion and reabsorption (rather than sodium excretion/reabsorption)
o Excretion of water is normally regulated independently of excretion of solute
o This means that the kidney must be able to excrete urine that is either hyperosmotic (retaining water) or hypo-osmotic (excreting water) with respect to ECF
ADH is synthesised from a peptide in the hypothalamus and packaged into the magnocellular neurones which project down into the posterior pituitary.
(Project to magnocellular neurons of paraventricular and supraoptic nuclei of hypothalamus)

Vasopressin will be secreted from the axon terminal when stimulated.

Question 15

What are the two physiological mechanisms that stimulate ADH release?

Answer 15

These are osmotic and haemodynamic.

Question 16

Where are osmoreceptors? Why there/why can it detect?
What causes ADH to be released in respect to osmoreceptors?

What detects haemodynamic changes which cause ADH release? Where are these sitauated? what do they detect? When do these receptors/responses come into play?

Answer 16

Osmotic
o There are osmoreceptors in the hypothalamus where the BBB is a bit leaky and they can signal changes in osmolality
o As plasma osmolality increases, we see an increase in ADH secretion
o Over the normal range, we have about a linear release of ADH
o As osmolality drops, ADH release drops and below 280mOsm it gets switched off.

Haemodynamics
o This is the other signal for ADH release, it is especially regulated by stretch receptors in left atrium of the heart, they are often called volume receptors. They detect pressure but in particular losses in pressure
o Losses in blood volume would be associated with acute drop in BP, this would signal volume depletion
o This effect of Haemodynamics stimulating ADH release doesn’t come into play until BP drops quite significantly.

So, this Haemodynamics response is not really to do with osmoregulation but more of a second line of defence against volume depletion. Remember that volume regulation is to do with Na+ and that the first line of defence against volume-depletion is aldosterone.

Question 17

What happens when BP drops? What mechanisms will be in play? How is BP kept high? when will body stop one of these mechanism?

Answer 17

In this situation of loss of BP, we would already have RAAS going but then ADH comes in to help if necessary.

So, if we have severe blood loss, Ang II will start vasoconstricting. Aldosterone will start bringing in Na+ and draw in water with it, to replete blood volume.
If blood loss is serious, then BP will be low, so we get ADH release which will result in more water reabsorption and vasoconstriction.

This would cause osmolality to start falling, so osmoreceptors will be telling the brain to STOP releasing ADH, however the brain will listen to the haemodynamics and continue to release to try raise BP.

Question 18

ADH increases water permeability in the collecting duct

what happens to tubular fluid from LoH to DCT?
what happens at CD if permeable to water?

What happens when ADH is in circulation? binds where on where? activates what? leads to>

what happens in absence of ADH to aquaporins? what happens when ADH is present?

Answer 18

The LoH dilutes the tubular fluid, as it moves up it gets progressively diluted. So is maximum dilution at DCT.

As it goes through the collecting duct which passes through the medulla (which is very hyperosmotic), water will move from the collecting duct out, if the collecting duct is permeable to water.
o So ADH regulates the membrane insertion of protein channels called aquaporins into the luminal membrane.

When ADH is in the circulation, it binds to its receptor (V2) on the basolateral membrane, it activates the AC intracellular pathway leading to increase cAMP and increase PKA.
In the absence of ADH, aquaporins are in vesicles, but when ADH binds it causes translocation of these vesicles to the luminal membrane where the aquaporins are inserted.

Water can then flow down its osmotic gradient, from the more dilute filtrate into the more concentrated interstitial tissue (and thus blood).

Question 19

What level does the vasopression system maintain plasma osmolarity at?

What is the solute load? Estimated amount?
Min volume of urine exceted? why is it this value?
Min conc of urine excreted? How much volume of urine?
What if kidney excretes more or less?

Answer 19

Normally the vasopressin system can maintain plasma osmolality at about 290mOsm/L, in the face of variable water intake.

Regardless of anything else (hydrated, dehydrated etc.) the kidney must excrete a certain amount of metabolic waste product in solute form (dissolved in water), this is the solute load.

The solute load is estimated as 10x BW(kg) (e.g. 600mOsmol/L for 60kg person, so this person MUST excrete this amount per day).
The max concentration of urine would be that of the conc. of the tip of the loop of Henle, this means it would be 1200mOsmol/L, so you can excrete out that 600mOsmol of solute in 0.5L of fluid, so this is the minimum volume of urine that can be excreted for this person.
The minimum concentration of urine would be that at the beginning of the DCT as you don’t bother reabsorbing anything, this could be 100mOsmol or even less, so to get rid of 600mOsmol you would have to get rid of 6L of urine.
Therefore, the kidney can concentrate urine to conserve water and dilute urine to excrete water but only within these limits. If you push beyond these, it will lead to either:
o Dehydration
o Over-hydration

Question 20

Thirst and Water Intake

What is hyperosmotic thirst? What is the physiology behind this?

What is hypovolumic thirst? What is the physiology behind this?

What else does dehyration lead to? (physiological findings)

Answer 20

Thirst is the first (and highly effective) line of defence against dehydration. Thirst can physiologically be divided into

A. Hyperosmotic thirst
• Rise in Na+ due to loss of water, stimulating hypothalamic osmoreceptors to release ADH, but the osmoreceptors also link up to other neuronal pathways which promote sensation of thirst

B. Hypovolemic thirst
• A loss of blood volume, stimulates RAAS, Ang II has actions on hypothalamic neurons which link onto thirst networks

Dehydration will also result in other physiological things such as decreased flow of saliva leading to a dry mouth which will also stimulate thirst.

Question 21

Abnormalities in water balance

What does effect of chnages on water intake and excretion primarily effect when looking at abnormalities in water balance?

Difference between osmalality and osmolarity?

consequences of abnormalities?

How do you get water excess?
How do you get water depletion?

Answer 21

To understand how abnormalities of water balance arise it is important to understand the effect of changes on water intake and excretions on:
• Osmolality of the ECF
• Plasma sodium concentration

Osmolality relates to the number of particles per unit volume of solution
o	Osmolality: per Kg solution
o	Osmolarity: per litre solution
Consequences:
•	ADH secretion and action
•	Renal water excretion

Water Excess

• Caused by excessive water intake
• Or impairment in renal excretion (E.g. SIAH)

Water depletion

• Insufficient water intake
• Excessive water loss

Question 22

Hyponatremia and Hypo-osmolality

What is hyponatremia associated with? What is true hypnoatremia?
How does the body respond to hypoatremia?
Consequences to hypnoatremia?
What causes hypoatremia?

Low serum soidum, plasma osmalality and concentrated urine + mass in lungs, what is this an indication of? What is the name of the disease?

What does excessive ADH do? What could this be caused by?

Answer 22

Hyponatremia is associated with hypo-osmolality as Na+ is the principle cation in the ECF.

True hyponatremia is an excess of water rather than a lack of Na+ because osmoregulation is to do with water.

If plasma Na+ < 135mmol/L (normally 135-145), then you have hyponatremia, the body doesn’t say whoa better absorb some Na+, it says whoa better excrete some water.

Because, the pathophysiology of hyponatremia is the effects of hypo-osmolality, with water moving into brain cells causing neurological damage.

Continued water intake with failure to suppress ADH (or beyond kidneys ability to excrete urine) can lead to water overload and hyponatremia, some examples of this include:
• Recent GI or cardiothoracic surgery
• Certain drugs (e.g. cyclophosphamide)
• Ectopic secretion of ADH

Low serum [Na+] so hypo-natremic, a low plasma osmolality and relatively concentrated urine (still absorbing water).
o This suggests a lung tumour producing ADH, an ectopic source of ADH.
o This is syndrome of inappropriate ADH secretion (SIAH).

Excessive ADH reduces the urinary excretion of water, this results in a state of water excess and
• Low plasma sodium
• Low plasma osmolality
• High urine osmolality

As stated could be due to tumour, a CNS disturbance (enhanced ADH release, stroke etc.) or due to drugs (enhanced release of ADH or response to it)

Question 23

Water Depletion (Dehydration)
Result of what 2 things?
What can cause increased loss of water?

Answer 23

Water depletion may result from two things:

Water depletion from decreased intake of water, may occur in
o	Infants
o	Elderly
o	Individuals in coma
o	Individuals with no access to water

Water depletion from increased loss of water through the kidney can occur in
o Diabetes mellitus (once blood glucose levels start rising beyond the level the kidney can secrete you get osmotic diuresis)
o Impairment of ADH release and or/action (insipidus)

Question 24

A case of polydipsia and polyuria

(normal plasma sodium levels but very low urine osmolality) -> what is this an indiaction of?

Complains of frequent urination and drinks large volume of water. why?

What is 2 ways diabetes insipidus is caused? How do these come about?
what are the major symotoms?

How do you distinguish between the two different causes?

Answer 24

The above persons plasma sodium is normal, yet their urine is extremely dilute. This suggests they are not re-absorbing water at all really, meaning lack/not responding of/to ADH.

There is water loss. The reason he is very thirsty, is that he is losing a lot of water and because of drinking so much he has managed to maintain his plasma sodium concentration.

Diabetes Insipidus may be caused by:
o A lack of secretion of ADH (called central DI) caused by genetic mutations, head trauma and disease of hypothalamus/pituitary region)

o Impaired response to ADH in the kidney (called nephrogenic DI). caused by mutation of ADH receptor, mutation of ADH-dependent H2O channels, renal disease or drugs

Major symptoms are:
o Polyuria
o Polydipsia
o Thirst

You distinguish between the two, using a Water Deprivation Test.
o Where you make someone dehydrated, if normal the persons urine should have a high osmolality and blood plasma normal.
o If the persons urine is still dilute (very low osmolality), then this person has DI.
o To distinguish between the two we give DDAVP, if its corrected then it is central if not then it is nephrogenic.

Question 25

Summary of Key Points

Answer 25

• Under normal conditions, water balance (osmoregulation) is regulated mainly by the ECF osmolality, ADH and renal water excretion.
• Abnormalities of water balance are common and can arise from a number of causes
• A knowledge of serum sodium concentration and plasma/urine osmolality are useful to understand the nature and problems of water imbalance
• Impairment of ADH secretion and or action is important cause of abnormal water balance

Question 26

Defences against dehydration: thirst

chnages detected by?
project to where? mediate what?

what reduced thirst on drinking?

2 other things thats stimulate thirst?

Answer 26

Net water loss increases ECF osmolarity

Normal range 285-295 mOsm/kg

Changes detected by osmoreceptors in anterior hypothalamus

Project to centres mediating thirst, drinking

Strong desire to drink when plasma osmolality ≥295 mOsm/kg

Oropharyngeal and upper gastrointestinal receptors reduce thirst on drinking

Thirst is also stimulated by

• Large (10-15%) drops in blood volume/pressure
• Angiotensin 2 acting on hypothalamus