Potassium Balance

Question 1

What is the difference between acute and chronic potassium regulation?

Answer 1

Acute regulation:
Distribution of K+ between intra- and extra-cellular fluid compartments
i.e. largely internal K+ balance
Chronic regulation:
Achieved by the kidney adjusting K+ excretion & reabsorption
i.e. largely “output part” of external K+ balance

Question 2

What are the functions of potassium?

Answer 2

Determines intracellular fluid osmolality
→ impacts on cell volume
Determines resting membrane potential (RMP)
→ very important for normal functioning of excitable cells
i.e. repolarisation of myocytes, cardiomyocytes & neurons
Affects vascular resistance which impacts blood flow

Question 3

How does a sodium/potassium pump work?

Answer 3

> 95% of bodily K+ is located intracellularly and only 2.5% is found in ECF
Na+-K+-ATPase pump maintains:
HIGH intracellular [K+] &
LOW intracellular [Na+]

Question 4

How is potassium internally balanced?

Answer 4

ECF pool will change more dramatically with changes in body K+ distribution
e.g. after a meal, get slight increase in plasma [K+], which is shifted into ICF compartment
Shift mainly subject to hormonal control:
Insulin
Adrenaline
Aldosterone
pH changes
VERY IMPORTANT that plasma [K+] remains in the right range

Question 5

What is the difference between hyper and hypokalaemia?

Answer 5

Clinical conditions defined as:
Hyperkalaemia= plasma [K+] > 5.5mM
Hypokalaemia= plasma [K+] < 3.5mM

Question 6

What is the resting membrane potential?

Answer 6

Resting membrane potential (RMP)
Membrane potential formed by creation of ionic gradients
(i.e. combination of chemical & electrical gradients)

E = RT ln [X]o EK = 61.5 × log [K]o ENa= 61.5 × log [Na]o
zF [X]i [K]i [Na]I
All you need to know is that this potential difference is a function of the ratio between the external potassium concentration and the internal potassium concentration
Normal RMP maintained by dynamic balance between Na+ and K+ concentrations

Question 7

What happens when plasma [K+] is altered above or below normal?

Answer 7

EK = 61.5 × log [K]o
[K]i
Normal: [K]o = 4.5mM and [K]i = 140mM ⇒ EK = -91.8 mV
Hyperkalaemia: [K]o = 7mM and [K]i = 140mM ⇒ EK = -80 mV
Hypokalaemia: [K]o= 1.5mM and [K]I = 140mM ⇒ EK = -121.5 mV
Can severely affect cardiomyocyte membrane potential producing characteristic changes in ECG

Question 8

What do hyper and hypokalaemia look like on an ECG?

Answer 8

Hypokalaemia: ↓ amplitude T-wave, prolong Q-U interval, prolong P-wave
Hyperkalaemia: ↑ QRS complex, ↑ amplitude T-wave, eventual loss P-wave

Question 9

How does a change in [K+] affect action potentials?

Answer 9

What happens when you have a low external potassium concentration is that you end up with a hyperpolarisation of the cell so that RMP has come down meaning the cell is a lot further away from the threshold- less excitable
A high potassium concentration ends up with a raised RMP which is a lot closer to the threshold- more excitable

Question 10

What is hypokalaemia?

Answer 10

Caused by renal or extra-renal loss of K+ or by restricted intake, e.g.:
Long-standing use of diuretics w/out KCl compensation
Hyperaldosteronism/Conn’s Syndrome
(↑↑ aldosterone secretion)
Prolonged vomiting → Na+ loss → ↑aldosterone secretion → K+ excretion in kidneys
Profuse diarrhoea (diarrhoea fluid contains 50 mM K+)
Hypokalaemia results in:
↓ Resting membrane potential
↓ Release of adrenaline, aldosterone & insulin

Question 11

What is hyperkalemia?

Answer 11

cute hyperkalaemia normal during prolonged exercise
Disease states:
Insufficient renal excretion
Increased release from damaged body cells eg. during chemotherapy, long-lasting hunger, prolonged exercise or severe burns
Long-term use of potassium-sparing diuretics
Addison’s disease (adrenal insufficiency)
Plasma [K+] > 7mM life-threatening → asystolic cardiac arrest
Treated with Insulin/Glucose infusion used to drive K+ back into cells
Insulin extremely important – mechanism unclear, may stimulate Na-K-ATPase. Why is glucose given with it?
Other hormones (aldosterone, adrenaline) stimulate Na+-K+ pump
⇒ ↑cellular K+ influx

Question 12

How is potassium externally regulated?

Answer 12

In a healthy person, external K+ balance is maintained almost entirely by the kidney
K+ excretion in the stools is not under regulatory control
(i.e. large amounts can be lost by extra-renal routes)
Maintenance of normal K + homeostasis increasingly important limiting factor in the therapy of CVD
Drugs like β-blockers, ACE inhibitors etc ↑ serum [K +]
⇒ ↑ risk of hyperkalemia
Conversely, loop diuretics used to treat heart failure
⇒ ↑ risk of hypokalaemia

Question 13

How have human kidneys evolved?

Answer 13

Human kidneys have evolved to: 
Conserve Na+
Excrete K+
 Na+ & K+ filtered freely at glomeruli
 Plasma & GF have same [Na+] & [K+]
 In 24h, entire glomerular filtrate (~180 litres) contains: 
 25 moles Na+ (= 1.5 kg NaCl)
 0.7 moles K+ (= 50 g KCl)*
	*depends on dietary intake

Question 14

What happens to Na+ and K+ in the proximal CT?

Answer 14

This is where the majority of both sodium and potassium ions are reabsorbed
Fractions that is reabsorbed in PCT is constant in a healthy person
But the absolute amount reabsorbed varies with the GFR
How is it reabsorbed?
So there is the regular sodium-potassium pump that maintains the low sodium level inside the cell so that we get the sodium gradient from the tubular lumen into the intracellular fluid
This allows other factors such as AA, glucose and phosphate can pass with it via symporters
And H+ can leave into the GF (tubular lumen) via an antiporter
This creates a problem as now there is a high concentration of K+ inside the epithelial cell

Question 15

What is K+ movement like in the proximal CT?

Answer 15

So as the fluid moves from the tubular lumen into the epithelial cell you get an increase in Cl-, K+ (sodium doesn’t increase but is still relatively high)
So what happens with the K+ is that we end up with diffusion between the cells through the gap junctions there is a passive paracellular process

Question 16

What is Na+/K+ movement in the loop of Henle?

Answer 16

Here, the GF enters, descend where water diffuses out
As it ascends sodium diffuses but then is pumped out
These pumps that remove NaCl is that it is a three way transporter that transports sodium, chloride and potassium
All driven by the sodium gradient
So there is a net movement of potassium from the GF in the tubular lumen into the epithelial cells and then into the ECF via a concentration gradient
Loop diuretics target this

Question 17

What is K+ movement like in the distal CT?

Answer 17

> 90% of filtered K + reabsorbed in PCT & LoH
Excretion of K + into urine by overload is controlled by K+ secretion by principal cells of late DCT & CD
So again we have the sodium potassium ATPase creating a high concentration of K+
Ordinarily the K+ would leak back into the ECF but in the principal cells it can leak into the GF
Augmented by the activation of an epithelial sodium channel called ENaC (activated by aldosterone)
This entry of sodium ions changes the electrochemical gradient so that the potassium will pass from the intracellular space into the fluid of the tubule
There is a second mechanism by which this can be done and that is via chloride potassium symporters

Question 18

What determines K+ secretion in DCT?

Answer 18

Increased K+ intake
Changes in blood pH
Alkalosis ⇒ ↑ excretion of K+ ⇒ ↓ serum [K+]
Acute Acidosis ⇒ ↓ excretion of K+ ⇒ ↑ serum [K+]
How is this achieved?
-activity of Na-K-ATPase pump
-electrochemical gradient
-permeability of luminal membrane channel

Question 19

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

Answer 19

↑ Plasma [K+] increases K+ secretion in 3 ways:
Slows exit from basolateral membrane
	⇒ ↑ [K+]i 
	⇒ cell-lumen concentration gradient 
↑ activity of Na+/K+ ATPase 
	⇒ ↑ [K+]i
Stimulates aldosterone secretion

Question 20

How does aldosterone affect potassium?

Answer 20

Aldosterone is the major regulator of potassium balance in the body
Increase in plasma K which detected in the cortical regions of the adrenal gland, the adrenal cortex, stimulates an increase in aldosterone
Increase in plasma aldosterone has an effect on the cortical collecting ducts and the DCT to increase K+ secretion into urine
Elevated potassium plasma levels also have this effect

Question 21

What is the aldosterone mechanism of action?

Answer 21

Aldosterone acts to:
↑ activity of Na+/K+ pump
⇒ ↑K+ influx
⇒ ↑[K+]i 
⇒ cell-lumen concentration gradient 
↑ ENaC channels 
⇒ ↑ Na+ reabsorption 
⇒ ↓ cell negativity and ↑ lumen negativity 
⇒ voltage gradient
Redistributes ENaC from intracellular localization to membrane 
↑ permeability of luminal membrane to K+

Question 22

How do alkalosis and acidosis affect potassium regulation?

Answer 22

In a high plasma pH environment (alkalosis) the activity of the ATPase on the basolateral side of the epithelial cell is elevated such that we get a rise in the intracellular concentration of potassium which favours its secretion
This is promoted by the movement of sodium into the cell
Conversely, in a low pH environment (acidosis(acute)) we get an inhibition of the sodium/potassium ATPase pump
Correspondingly we get a decrease in the K+ concentration within the cell such that the electrochemical gradient is no longer favourable for potassium secretion

Question 23

How does tubular flow rate affect K+ secretion?

Answer 23

↑ Flow rate by:
-↑GFR
-Inhibition of re-absorption
-K-wasting diuretics
-ADH
All of these things have the effect of diluting the potassium
By diluting the potassium in the tubular lumen you are favouring the electrochemical gradient along which potassium ions can move
ADH facilitates the activity of the potassium channels to promote potassium secretion

Question 24

Why is K+ reabsorbed in severe hyperkalaemia?

Answer 24

α-Intercalated cells of late DCT/CD active to provide additional reabsorption of potassium
We have activation of a potassium hydrogen ATPase on the luminal apical membrane of this specialised epithelial cell thereby promoting additional potassium reabsorption

Question 25

How does homeostasis intercalate?

Answer 25

Dependence of potassium secretion on sodium and flow rate poses problems
Could coupling K excretion to distal flow rate jeopardize potassium balance?
Through these homeostatic mechanism this shouldn’t really happen
In this example we have a decrease in extracellular fluid volume (e.g. thirst)
You would get a higher concentration of potassium in the plasma which would promote aldosterone secretion
This promotes potassium secretion, but there is no benefit from this
The decrease in ECFV also leads to increased Na reabsorption in the proximal tubule, in fact augmented by the increased aldosterone
The increase in sodium reabsorption will lead to a decrease in flow rate in the tubules which will have the opposing effect on potassium secretion therefore unchanged potassium excretion

Question 26

How does the RAAS cascade integrate together?

Answer 26

Say there is a fall in BP detected by the juxtaglomerular apparatus
And a fall in Na detected by the macula densa in the tubules
These would signal a release of renin which through several chemical steps lead to a release of aldosterone
Aldosterone on the principal cells promotes sodium reabsorption and potassium secretion creating a gradient in which water can be reabsorbed which addresses those two factors
Aldosterone also affects the intercalated cells where it promotes potassium and sodium reabsorption and hydrogen secretion
Angiotensin II also promotes vasoconstriction which raises BP
It also inhibits renin through negative feedback
A high potassium concentration in plasma also triggers aldosterone secretion

Question 27

What is the function of the adrenal cortex?

Answer 27

Adrenal Cortex produces:
Glucocorticoid hormones (e.g. Cortisol)
Sex hormones (androgens & oestrogens)
Mineralocorticoid hormones 
(e.g. Aldosterone)

Question 28

What is Addison’s disease?

Answer 28

Primary Adrenal Insufficiency
Rare compared to secondary adrenal insufficiency (diseases that themselves cause impairment of adrenal function)
Damage to cortex
⇒ ↓↓ hormone production
⇒ numerous symptoms
Deficiency in aldosterone
⇒ body secreting large amounts Na
⇒ low serum Na levels
⇒ body retaining K
⇒ hyperkalaemia
Treatment usually involves corticosteroid (steroid) replacement therapy for life.

Question 29

What is the secondary adrenal insufficiency?

Answer 29

The pituitary gland normally makes adrenocorticotropin (ACTH)
If you have a condition that leads to the decrease in ACTH
Ultimately your adrenal glands will shrink so that you can no longer produce the hormones needed

Question 30

What is Conn’s syndrome?

Answer 30

Primary Aldosteronism aka Conn’s Syndrome
Due to aldosterone-producing adenoma of adrenal gland zona glomerulosa 
Usually <3cm, unilateral & renin-unresponsive
Hyperaldosteronism (excess release of aldosterone) due to variety chronic disease
Most commonly (50-60%) due to Conn’s syndrome, remaining 40-50% due to bilateral adrenal hyperplasia
Aldosterone release in absence of stimulation by Angiotensin II, no control mechanism

Question 31

How does Conn’s syndrome present?

Answer 31

↑↑↑ Plasma Aldosterone
⇒ kidneys to stimulate Na+ reabsorption & K+ excretion
⇒ develop hypertension*
⇒ ↑ fluid volume
⇒ hypokalaemia, hypernatremia and alkalosis (↓K+ ↑Na+ ↑pH)
* ↑ bp & Na delivery to macula densa
⇒ ↓↓ release of renin
⇒ renin-independent cause of hypertension (very difficult to control)
Treatment:
-surgical removal of tumour-containing adrenal gland
-hypertension & hypokalaemia controlled with K+-sparing agents e.g. spironolactone