S2: Potassium Balance

Question 1

Describe potassium input

Answer 1

• Found in leafy vegetables, most fruit and potatoes
• Should not be restricted routinely unlike sodium. Only in cases of renal impairment with low GFR. This is because many K+ foods are healthy

Question 2

Describe potassium homeostasis (internal and external balance)

Answer 2

Most of the potassium in the body is found within cells

Internal balance= Regulation between the intracellular and extracellular compartments of potassium is done by 3Na+/2K+ ATPase pump. The hormones that effect this balance include insulin, adrenaline, aldosterone and it can be affected by pH.

External balance = homeostasis that occurs between what is taken into the body in diet and what is excreted. Kidneys play a major role in this. External balance regulates urinary K+ excretion/retention which affects K+ balance in body.

Loss of K+ occurs in stool and sweat but this is unregulated.

Question 3

What are the 2 types of regulation of K+ homeostasis?

Answer 3

1. Acute regulation - distribution of K+ through the ICF and ECF
2. Chronic regulation-acheived by kidneys adjusting K+ excreting and reabsorption

Question 4

What are potassium’s functions that make it so important that we have to regulate it in this way?

Answer 4

• It levels are so high intracellularly it has an important role in determining intracellular fluid osmolality and hence cell volume
• Determines RMP (K+ leaking out). It is important for functioning of excitable cells i.e. the repolarisation of certain cells like myocardial, skeletal muscle and nerve cells
• It affects vascular resistance

Question 5

What does the Na+/K+ ATPase pump do?

Answer 5

The Na+/K+ ATPase pump maintains high intracellular [K+] and low [Na+] by pumping 2K+ in for every 3Na+ out. It utilises ATP to do this.

Question 6

Describe Internal balance

Answer 6

After we eat a meal, our [K+] levels in our plasma rise. This needs to be quickly shifted into ICF compartment (because EC pool will change more dramatically with changes in K+). This shift is mainly due to hormonal control and uses Na+/K+ ATPase pump.

Question 7

List factors that control internal balance/acute regulation

Answer 7

Insulin
Adrenaline
Aldosterone
PH changes

They all act to push potassium into cells

Question 8

Hyperkalemia and Hypokalemia levels

Answer 8

Plasma [K+] > 5.5mM = Hyperkalemia
Plasma [K+] <3.5mM = Hypokalaemia

It is VERY important that plasma [K+] doesn’t rise above 6.5mmol/L,

Question 9

What gradient does RMP rely on?

Answer 9

Our cells rely on the creation of an ionic gradient for the membrane potential.
An ionic gradient is two gradients combined, the combination of chemical and electrical gradients.

It is mainly Na+ and K+ that determine these gradients though ions such as Cl- contribute

Question 10

What is the Nerst Equation? (Ek)

Answer 10

The Nerst equation tells us the equilibrium potential (i.e. when net movement stops) and we can use this to calculate the membrane potential.
Ek= 61.5 x log [K]o/ [K]i

Question 11

What is the relationship of RMP and hyper/hypokalemia?

Answer 11

It can be seen in hyperkalemia, the equilibrium potential for K+ is more positive, i.e. so RMP is closer to a position of depolarisation.

When you drop the K+ equilibrium potential in hypokalemia you move the RMP closer to hyperpolarisation.

Question 12

Consequences of change in RMP

Answer 12

Changes in RMP can severely affect the heart, this is by causing cardiac cell membrane potential depolarisations/hyperpolarisations, this produces characteristic changes in ECG.

Question 13

K+ and AP

hyper and hypokalemia

Answer 13

So in the case of LOW potassium, hypokalemia, you will have more K+ moving out of the cell because there is less in the plasma (so greater gradient and lower +charge pushing it in). As a result the equilibrium potential will be much more negative, so RMP (when add on Na+) will be more negative than normal.
I.e. the cell will be permanently hyperpolarised, so it has to travel much more to breach threshold.
So this would evidently effect the cell that needs to depolarise.

In the case of HIGH potassium, hyperkalemia, you will have less K+ moving out your cell due to increased K+ in plasma (so decreased gradient and increased + charge pushing it in). So cell will be more positive and equilibrium potential will be much more positive than normal.
This means the cell may end up being more permanently or very easily depolarised so it does it fires AP more sporadically.

Question 14

Describe hypokalemia

Causes

Answer 14

Hypokalaemia may be caused by renal or extra renal loss (stool, sweat) of K+ or by restricted intake

Examples:

• Long standing use of diuretics without KCl compensation
• Conn’s syndrome
• Prolonged vomiting = increased adosterone secretion = increased K+ excretion in kidneys
• Profuse diarrhoea
• Loop diuretics, used to treat heart failure, enhance the risk of hypokalemia

Hypokalemia results in decreased release of adrenaline, aldosterone and insulin, in order to prevent shifting into the cell.

Question 15

Describe hyperkalemia

Causes

Answer 15

Acute hyperkalemia is normal following prolonged excersize as muscle breaks down (and muscle cells contain high K+) and it gets released into plasma.

Example:

• Insufficient renal excretion
• Increased release of K+ from damaged body cells (e.g. during chemo, starvation, prolonged excersize or severe burns)
• Addisons disease
• various drugs like beta-blockers, ACE inhibitors etc. raise serum [K+], increasing risk of hyperkalemia

Question 16

List some treatments of hyperkalemia

Answer 16

Insulin/glucose infusion to drive K+ back into cells.
Insulin is extremely important but the mechanism however is unclear, it may stimulate the Na+/K+ pump. Glucose is given with it to prevent hypoglycemia (which would occur with infusion of insulin).

Other hormones (aldosterone, adrenaline) can also be used which would stimulate Na+/K+ and increase cellular K+ influx.

Question 17

Describe external balance/chronic regulation

Answer 17

Balanced by the kidney

Maintenance of normal K+ homeostasis is increasingly important limiting factor in the therapy of CVD

Question 18

Why are human kidneys designed to conserve Na+ and excrete K+?

Why is our kidneys not efficient for modern day diet?

Answer 18

Prehistoric humans consumed Na+-poor and K+-rich diet (many fruit), hence humans kidneys are designed to conserve Na+ and excrete K+. Evolution of our kidneys is not efficient for modern day diet as we consume high amounts of salt which the kidney retain.

Question 19

Explain K+ and Na+ filtering at glomerulus

Answer 19

Both Na+ and K+ are filtered freely at the glomeruli. So, plasma and GF have same [Na+] and [K+].

Question 20

How much Na+ and K+ is reabsorbed at PCT?

Answer 20

• 60-70% of Na+ and K+ is reabsorbed in the PCT

- Fraction reabsorbed is always kept constant but absolute amount reabsorbed varies with GFR

Question 21

Explain Na+ and K+ movement in PCT

Answer 21

[Na+] high in tubular lumen so it is reabsorbed down its conc gradient carrying various other substances with it (AA,glucose,phosphate symporter with Na+).

On the basolateral side of the membrane, Na+/K+ is maintaining the gradient and pumping K+ into tubular cells. K+ conc is high in cell so it will diffuse down its concentration gradient through ‘leak’ channels back into blood

• Cl-, K+ and Na+ also passively diffuse into blood via paracellular route through the tight junctions. As they do this, water follows so anything dissolved in water also moves.

Question 22

Explain Na+ and K+ movement in LoH

Answer 22

In the thick ascending limb, there is a Na/2Cl/K+ symporter present on the luminal membrane (from lumen to cell). This is driven by the [Na+] gradient from lumen to cell (there is an Na+/K+ ATPAse on basolateral). There is also an Na+/H+ antiporter on luminal side.

On basolateral side, as said you have the Na+/K+ pump. As there will be a lot of K+ in the cell there is a lot of movement out of the cell into blood, contributing to interstitial fluid making it hyperosomotic, it will also diffuse in vasa recta and small amount into descending limb.

Question 23

Explain K+ movement in DCT

Answer 23

Principle cells of late DCT and CD are able to secrete K+ into tubule for excretion into urine.

Na+/K+ ATPase pump on basolateral membrane

Na+ channels on lumincal/apical membrane that are aldosterone sensitive known as ENaC channels. Na+ flowing into the cell alters the electrochemical gradient so that it favours movement of K+ from blood into lumen.

K+/Cl- symporter on luminal membrane kicking out K+.

Question 24

What can inhibit ENaC?

Answer 24

K sparing dieuretics e.g. amiloride

They inhibit K+ excretion as electrical gradient using Na+ cannot be altered

Question 25

What factors determine K+ secretion in DCT?

Answer 25

- Increased K+ intake - Changes in blood PH Alkalosis increases excretion of potassium and decreases serum [K+] Acute acidosis decreases excretion of K+ and so increases serum [K+]

Question 26

What 3 things are altered to cause a switch between K+ secretion and reabsorption in DCT?

Answer 26

- Activity of Na+/K+ pump - Alter electrochemical gradient - Alter permeability of luminal membrane channel

Question 27

Explain aldosterone and K+ secretion

Answer 27

Aldosterone is the major regulator of K+ balance in the body - Aldosterone increases the activity of the 3Na+/2K+ pump so it increases the K+ influx into cell. This increase in cell lumen conc. so K+ will have movement out - Aldosterone also increases activity of ENaC channels so this means increased entry of Na+ into cell which favours movement of K+ into lumen - It also redistributes ENac from intracellular localisation to membrane - It increases permeability of luminal membrane to K+ Aldosterone=increase K+ secretion and therefore excretion

Question 28

How does increase plasma [K+] increase K+ secretion?

Answer 28

1. Slow exit of K+ from basolateral membrane (into plasma) because the concentration gradient is reduced by high plasma [K+] 2. Increases activity of Na+/K+ pump so increasing intracellular K+ so it moves out of luminal membrane 3. Increased plasma [K+] also stimulates aldosterone secretion

Question 29

How does potassium stimulate aldosterone secretion?

Answer 29

Increased potassium intake --> Increase plasma K+ --> Increase aldosterone secretion from adrenal cortex --> Increase plasma aldosterone --> Increase K+ secretion from coritcal collecting ducts (this also increases plasma K+) --> Increase K+ excretion

Question 30

How does alkalosis/acidosis affect K+ secretion and excretion?

Answer 30

Alkalosis An increase in plasma PH results in increased activity of Na+/K+ resulting in increased [K+] in the cell hence favouring the concentration gradient for K+ secretion. Acute Acidosis Increase in [H+] in ECF reduces the activity of Na+/K+ pump, resulting in decreased intracellular [K+]. This will reduce passive diffusion of K+ and hence reduce secretion of K+ into tubule.

Question 31

Explain tubular flow rate (V*) and K+ secretion

Answer 31

Increased flow rate may result from increase GFR, inhibition of resorption upstream or diuretics (K+ wasting. This will sweep away secreted K+ making local tubular fluid [K+] low thus causing a more rapid rate of net secretion due to the [K+] gradient favouring it from cell lumen

Question 32

Does ADH affect K+ secretion?

Answer 32

Yes | It has a small effect on the luminal permeability of K+ but not as much as aldosterone

Question 33

What happens to K+ in late DCT and CD during severe hypokalaemia?

Answer 33

During severe hypokalaemia, reabsorption of K+ in late DCT and collecting duct mainly occurs in a-intercalated cells. It normal conditions, this does not happen and reabsoption occurs in PCT and LoH. The mechanism by which reabsorption occurs is not well understood but the intercalated cells may have a K+/H+ ATPase pump on the luminal membrane with H+ excretion and K+ reabsorption. It is active in severe hypokalaemia, where you really want to build up K+ in the plasma.  

Question 34

How is K+ balance kept stable despite fall in ECFV?

Answer 34

A fall in ECFV will lead to increased Na+ and fluid reabsorption in PCT (to plasma) which would decrease distal K+ secretion because of a decline in delivery fluid (flow rate) and Na+ to principle tubule cells hence K+ secretion into urine should decrease. Reduction in ECFV also stimulates the release of aldosterone which stimulates distal K+ secretion. It also stimulates increase Na+ reabsorption (therefore decreased V* and decreased K+ secretion). Hence the change in potassium excretion is minimized. So as a result of these opposing effects K+ excretion remains relatively constant.

Question 35

Explain how low BP and low Na+ affect RAAS

Answer 35

Low BP --> Stimulates juxtaglomerular apparatus Low Na+ --> Stimulates macula densa cells Both these things act to secrete renin, renin leads to formation of angiotensin II. Ang II causes vasoconstriction to raise BP. It also leads to the release of aldosterone from zona glomerulosa of adrenal cortex. Aldosterone will act on the distal tubules to increase Na+ reabsorption, it does this by increased Na+/K+ activity and increased ENaC on luminal membrane. Increasing Na+ also increases water reabsorption, this allows to restore BP and the Na+ levels. Aldosterone can also act on other parts of the tubule, depending on the situation resulting in increased K+ reabsorption and increased H+ secretion because of stimulating the K+/H+ ATPase (-> could lead to alkalosis, increased pH). Remember also that high plasma K+ can stimulate aldosterone release.

Question 36

List Factors that shift K+ into cells | decrease extracellular [K+]

Answer 36

Insulin Aldosterone β-adrenergic stimulation Alkalosis

Question 37

List Factors that shift K+ out of cells (increase extracellular [K+])

Answer 37

Insulin deficiency (diabetes mellitus) ``` Aldosterone deficiency (Addison’s disease) ``` β-adrenergic blockade Acidosis Cell lysis Strenuous exercise Increased ECF osmolarity

Question 38

List some steroid that adrenal cortex produces

Answer 38

- Glucocorticoids (main one cortisol) - Mineralocorticoids (mainly aldosterone) Sex hormones (mainly androgens and oestrogens)

Question 39

Describe Addison's Disease

Answer 39

It is primary adrenal insufficiency where there is an actual improper functioning of the adrenal gland itself so they produce insufficient steroid hormones (all of them). This is rare. More common is secondary adrenal insufficiency which is a lack of pituitary release of ACTH (leading to adrenal shrinking) A deficiency in aldosterone means the body will be SECRETING large amounts of Na+, so there will be low serum Na+, consequently the body will be retaining K+ = hyperkalemia.

Question 40

Explain Conn's Syndrome What is hyperaldosteronism?

Answer 40

Primary Alsosteronism is excess release of aldosterone due to alsdosterone producing adenoma in zona glomerululosa of adrenal cortex. Usually renin unresponsive. Hyperaldosteronism is excess release of aldosterone and can be caused by a variety of chronic diseases e.g. Conn's syndrome, bilateral adrenal hyperplasia Very high plasma aldosterone, will stimulate kidney Na+ reabsorption to a very large level and thus K+ excretion! You end up developing hypertension and there is an increase in fluid volume (also increases BP). Due to kicking out so much K+ you develop hypokalemia, hypernatremia from reabsorbing so much Na+ and alkalosis (from stimulating H+/K+ antiport). Treatment is via surgical removal of the tumour. The hypertension and hypokalemia treated with K+ sparing agents e.g. spironolactone.