Flashcards in Potassium Balance Deck (28)
Describe the distribution of potassium in the body.
The concentration of K+ is high within the cells (~150 mmol/L) and low outside of the cells (~4.5 mmol/L). This difference is maintained by Na-K-ATPase.
Maintenance of the low ECF [K] is crucial. From moment to moment, the low ECF [K] is maintained mainly by internal balance, which shifts K+ between the ECF and ICF compartments.
The major factors that affect this balance are diet, urine, stools and sweat.
External balance refers to the entire body and is the balance between what is taken in via the diet and what is excreted out. In a healthy person, the external balance is maintained almost entirely by the kidney.
What does the regulation of K+ homeostasis imply?
- ACUTE REGULATION: distribution of K+ through the ECF and ICF compartments
- CHRONIC REGULATION: achieved by the kidney adjusting K+ excretion and reabsorption
List some of the functions of potassium.
1) determines the ICF osmolality, and thus cell volume
2) determines the resting membrane potential (RMP), which is very important for the normal functioning of excitable cells (ie. the repolarisation of myocardial cells, skeletal muscle and nerve cells)
3) affects vascular resistance
Describe the significance of the Na+-K+ ATPase pump.
It helps establish a net charge across the plasma membrane with the interior of the cell being negatively charged with respect to the exterior. This resting potential prepares the nerve and muscle cells for the propagaion of action potentials leading to nerve impulses and muscle contraction.
The accumulation of sodium ions outside of the cell draws water out of the cell and this enables it to maintain an osmotic balance (otherwise it would swell and burst from the inward diffusion of water).
Define the boundaries of hyperkalaemia and hypokalaemia.
The clinical conditions are defined as:
HYPERkalaemia = plasma [K+] > 5.5 mM
HYPOkalaemia = plasma [K+] < 3.5 mM
Describe how the resting membrane potential is related to the Nerst equation.
The membrane potential is formed by the creation of ionic gradients (ie. the combination of chemical and electrical gradients).
Nerst derived an equation that allows us to determine at which point the two forces (chemical and electrical gradients) balance each other - ie. at what point we have an ionic equilibrium.
What is the Nerst equation?
E = RT/zF ln[X]o/[X]i
E is the Nerst Equilibrium Potential, R is the ideal gas constant, T is the temperature in Kelvin, z is the charge of the ion (valance) and F is Faraday's number.
What happens the plasma [K+] is altered above or below normal?
It can severely affect the heart (cardiac cell membrane potential depolarisations and hyperpolarisations), producing characteristic changes in ECG.
How does [K+] affect action potentials?
low [K+] = hyperpolarisation
high [K+] = depolarisation
How do hyperkalaemia and hypokalaemia affect an ECG reading?
- lowered amplitude of the T wave
- prolonged Q-U interval
- prolonged P wave
- increased QRS complex
- increased amplitude of the t wave
- eventual loss of the P wave
Hypokalaemia is caused by a renal or extra-renal loss of K+ or by the restricted intake of K+.
- long-standing use of diuretics without KCl compensation
- hyperaldosteronism/ Conn's Syndrome (increased aldosterone secretion)
- prolonged vomiting, which leads to Na+ loss, which leads to increased aldosterone secretion, which leads to K+ excretion by the kidneys
- profuse diarrhoea (diarrhoea fluid contains 50 mM of K+)
Hypokalaemia results in the decreased release of adrenaline, aldosterone and insulin.
Acute hyperkalaemia is normal following prolonged exercise, as normally the kidneys will excrete the extra K+ easily.
We get the diseased states when:
- there is insufficient renal excretion
- there is the increased release of K+ from damaged body cells (eg. during chemotherapy, long-lasting hunger, prolonged exercise or severe burns)
- there is long-term use of potassium-sparing diuretics
- Addison's disease is present (adrenal insufficiency)
A plasma [K+] of > 7mM is life-threatening, as it can lead to asystolic cardiac arrest. An insulin/ glucose infusion is used to drive K+ back into cells. Other hormones (such as aldosterone and adrenaline) stimulate the Na+/K+ pump, so they increase the cellular K+ influx.
Describe external balance and chronic regulation of K+.
In a healthy person, the external balance is maintained almost entirely by the kidney.
The maintenance of normal K homeostasis is an increasingly important limiting factor in the therapy of CVD. Drugs like β-blockers and ACE inhibitors raise the serum [K+], thus increasing the risk of hyperkalaemia. Conversely, loop diuretics are used to treat heart failure, enhancing the risk of hypokalaemia.
K+ excretion in the stools is not under regulatory control, so large amounts can be lost by extra-renal routes.
Describe the renal handling of Na+ and K+.
Human kidneys are designed to conserve Na and excrete K.
Na+ and K+ are filtered freely at the glomeruli. Thus, the plasma and the GF have the same [Na+] and [K+].
Describe K+ movement in the PCT.
In the PCT, K+ reabsorption is passive and paracellular through tight junctions. The Na+/K+ pump in cell membranes maintains high intracellular [K+] and low intracellular Na. Also, there are many K and Cl channels through which ions leak out.
By the end of the early proximal tubule, essentially, all the glucose amino acids and much of the bicarbonate has been reabsorbed. This established a Cl- and K+ concentration gradient from the lumen to the peritubular fluid. The Na+ and K+ move passively along this gradient with Cl- in a paracellular route.
The gradient for Na+ entry across the luminal membrane is maintained by the Na/K ATPase pump. If this is inhibited (for eg., by dopamine, digitalis), then the Na gradient is dissipated, eventually losing primary Na transport and the associated secondary active solute transport. We also end up with NO osmotic gradient for water transport.
Describe Na+/K+ movement in the Loop of Henle.
The LoH creates a cortico-medullary osmotic concentration gradient in the medulla by the fact that the descending limb is very permeable to water but the ascending limb (thin and thick) isn't. Hence, as the fluid enters the descending limb and water leaves, the fluids gets more concentrated, reaching a peak of 1200 mOsm at the tip of the LoH. As it enters the ascending limb, characteristic changes occur and it is now impermeable to H2O but highly permeable to solutes. In the thin ascending limb, we get Na and Cl diffusing out. As we move up into the thick ascending limb, active reabsorption/ pumping of Na and Cl out of the fluid occurs, thereby making it more and more dilute.
This is done via a Na/2Cl/K symporter on the luminal membrane, which is driven by the [Na] gradient from the lumen-cell. We also have entry of Na from the Na-H antiporter. On the basolateral side, we have Na/K ATPase pump and the cotransport of Cl and K out of the cell (especially in the thick ascending limb). We will also probably get some diffusion of K back into the descending limb. Since there is no water movement, the fluid in the lumen is very diluted, such that by the time that it reaches the distal tubule, it is very hyposmotic (100 mOsm/L).
Describe K+ movement in the DCT.
The majority of K is reabsorbed. But, in order to balance the input and output, we also need to be able to excrete excess K into the tubule, and hence urine. Most of this occurs mainly in the principle cells of the distal tubule and collecting duct, as most of the day to day variation in k excretion is not due to changes in reabsorption that occurs in PCT or LoH.
So, if we have excess K and want to excrete it out, the K would enter the secreting cells from the blood via the Na-K-ATPase pump. It then diffuses from the cell down the electrochemical gradient through K+ channels that exist in the luminal/ apical membrane into the tubular fluid. The electric gradient across the luminal membrane normallu opposes the exit of K from the cell, but that gradient is reduced by the Na flux through the ENaC channel in that membrane (which, like the Na+/K+ transporter, is aldosterone-sensitive). Thus, the chemical gradient dominates. This is mainly why K+ secretion is coupled with Na+ reabsorption, ie. the more Na+ reabsorbed by the principle cell, the more K+ secreted.
A K-Cl cotransporter (symporter) also exists in the apical membrane and transports both K and Cl from the cell into the lumen.
What causes the switch between K secretion and reabsorption?
There are 3 determinants of K secretion control:
1) activity of the Na-K-ATPase pump
2) electrochemical gradient
3) permeability of the luminal membrane channel
What determines K+ secretion in the DCT?
- increased K+ intake
- changes in blood pH (alkalosis and acidosis)
How is aldosterone involved in K+ secretion?
Aldosterone is a major regulator of K balance in the body. It acts to:
- increase the activity of the Na+/K+ pump, which increases K+ influx, which increases intracellular [K+], which contributes to the cell-lumen concentration gradient
- increases ENaC channels, which increase Na+ reabsorption, which decrease cell negativity and increase lumen negativity, thus contributing to the voltage gradient
- redistributes ENac from its intracellular localisation to the membrane
- increases the permeability of the luminal membrane to K+
How does plasma [K] affect K+ secretion?
Increased plasma [K] increases K secretion in 3 ways:
- it slows its exit from the basolateral membrane, so increase intracellular [K+], so contributing to the cell-lumen concentration gradient
- increased activity of Na+/K+ ATPase, so increased [K+] within the cell
- increased plasma [K], so stimulated aldosterone secretion
How does alkalosis affect K secretion?
With alkalosis, the increase in plasma pH results in increased activity of the Na+/K+ pump, resulting in increased [K+] in the cell, hence favouring the concentration gradient for K secretion. Also, during alkalosis, we get an increase in tubular fluid pH (because proximal tubule H+ secretion is decreased, which increases HCO3- in the tubular fluid, so increasing the tubule pH) which increases the permeability of the luminal membrane.
In acute acidosis, the increase in [H+] of the ECF reduces the activity of the Na+/K+ pump, decreasing intracellular [K], reducing the passive diffusion of K and, hence, the excretion of K.
How does tubular flow rate affect K+ secretion?
With an increase in tubule fluid flow rate (resulting from increased GFR, the inhibition of reabsorption upstream or K+-wasting diuretics), secreted K is sweeped away, making the tubular fluid [K] low, which permits a more rapid rate of net secretion and maintains the [K+] gradient favourable to secretion.
With ADH, it stimulates K secretion by increasing the K conductance of the luminal membrane. However, the effect is not as great as that of aldosterone.
Where does the reabsorption of K+ occur?
It occurs mainly in the intercalated cells (late DCT and CD) - under normal conditions, it doesn't play much of a role since most of the reabsorption occurs in the PCT and LoH.
The mechanism is not well understood, but intercalated cells may have a H-K-ATPase pump with H excretion, resulting in K reabsorption. It is active in severe hypokalaemia.
In people on a low K+ diet, or suffering from K+ loss such as in diarhhea, events in the proximal tubule and the Loop of Henle occur as described before. In this condition, however, the distal tubule, the connecting tubule and the cortical collecting duct do not secrete K+, and may even reabsorb some K+. The K+ which passes through the cortical collecting duct is reabsorbed in the medullary collecting duct and K+ excreted in the urine is minimal.
How is K exceretion maintained with a fall in ECFV?
A fall in ECFV leads to increased Na and fluid reabsorption in the PCT. which would decrease distal K secretion because of the decline in delivery of fluid and Na to the principle tubule cells. Hence, K secretion into the urine should decrease.
But, the reduction in ECFV also stimulates the release of aldosterone, which stimulates distal potassium secretion. Hence, the change in potassium excretion is minimised.
As a result of these opposing effects, the K excretion remains relatively constant.
How does the RAAS system affect K secretion?
The RAAS system is normally considered sodium-retaining, but it is also important for the regulation of potassium and BP.
For example, the patient is ill with vomiting and low BP - the JGA senses the fall in local BP whilst the macula densa detects the low sodium load/concentration in the DCT. This leads to the release of renin, which leads indirectly to the formation of Angiotensin II. This, is turn, causes vasoconstriction and stimulates the adrenal cortex to produce aldosterone.
Aldosterone, in turn, acts on the DCT to increase Na reabsorption by increasing the activity and the insertion of more Na/K ATPase pumps, and increasing the number of ENaC channels. The incoming Na+ brings more water via osmosis, thus restoring fluid volume and pressure. This then leads to more K+ (or H+) secreted in exchange. Hence, aldosterone increases both the recovery of Na and the loss of K+ (or H+).
This is important because a high plasma [K+] itself causes the release of aldosterone from the adrenal cortex. The renin release is supressed by direct negative feedback from Angiotensin II.
Aldosterone also acts on the intercalated cells to increase the activity of the Na+/H+ antiporter, and thus influences the acid-base status of the body by increasing H+ secretion, so we can get an increase in serum pH.
(pay attention to the differing effects of aldosterone on potassium depending on which cells it's acting on)
Describe Adisson's Disease as a pathology related to Na and K balance.
Primary adrenal insufficiency (aka. Addison's Disease) means that there is damage to the cortex, so there is less hormone production, causing numerous symptoms.
This causes a deficiency in aldosterone, which leads to the body secreting large amounts of Na (leaving low serum Na levels) and the body retaining K (leading to hyperkalaemia).
The treatment usually involves corticosterois (steroid) replacement therapy for life.