Potassium Balance (Physiology)

✿ Distribution of potassium (K+) between intra- and extra-cellular fluid compartments.

Acute regulation largely involves maintaining internal K+ balance.

✿ Chronic regulation is primarily achieved by the kidney adjusting K+ excretion and reabsorption.

✿ Chronic regulation mainly involves the "output part" of external K+ balance.

✿ Determines intracellular fluid osmolality, affecting cell volume.

✿ Determines resting membrane potential (RMP), crucial for the normal functioning of excitable cells such as myocytes, cardiomyocytes, and neurons.

✿ Affects vascular resistance.

Intracellularly, accounting for over 95% of total potassium.

Only 2.5% of bodily potassium is found in the extracellular fluid (ECF).

✿ The Na+/K+ ATPase pump maintains a high intracellular concentration of potassium ([K+]) and a low intracellular concentration of sodium ([Na+]).

✿ The ECF pool will change more dramatically with changes in body K+ distribution.

✿ After a meal, there is a slight increase in plasma [K+], which is shifted into the intracellular fluid (ICF) compartment.

The shift is mainly subject to hormonal control, including insulin, adrenaline, aldosterone, and pH changes.

✿ It is very important for plasma [K+] to remain in the right range for proper physiological function.

Hyperkalemia is defined as plasma [K+] greater than 5.5mM.

Hypokalemia is defined as plasma [K+] less than 3.5mM.

✿ The resting membrane potential (RMP) is formed by the creation of ionic gradients, which is a combination of chemical and electrical gradients.

The normal resting membrane potential (RMP) is maintained by a dynamic balance between sodium (Na+) and potassium (K+) concentrations.

Alterations in plasma [K+] above or below normal levels can impact the resting membrane potential (RMP) and cellular function.

Normal: [K]o = 4.5mM and [K]i = 140mM ⇒ EK = -91.8 mV

Hyperkalemia: [K]o = 7mM and [K]i = 140mM ⇒ EK = -80 mV

Hypokalemia: [K]o= 1.5mM and [K]I = 140mM ⇒ EK = -121.5 mV

Alterations in potassium levels can severely affect cardiomyocyte membrane potential, producing characteristic changes in the electrocardiogram (ECG).

Hypokalemia can be caused by renal or extra-renal loss of potassium (K+) or by restricted intake, such as:

✿ Long-standing use of diuretics without potassium chloride (KCl) compensation

✿ Hyperaldosteronism/Conn’s Syndrome (increased aldosterone secretion)

✿ Prolonged vomiting leading to sodium (Na+) loss and increased aldosterone secretion, resulting in potassium (K+) excretion in the kidneys

✿ Profuse diarrhea (diarrhea fluid contains 50 mM K+)

Hypokalemia results in a decrease in resting membrane potential and a decrease in the release of adrenaline, aldosterone, and insulin.

Hyperkalemia can be caused by various disease states and factors, including:

✿ Insufficient renal excretion

✿ Increased release from damaged body cells (e.g., during chemotherapy, long-lasting hunger, prolonged exercise, or severe burns)

✿ Long-term use of potassium-sparing diuretics

✿ Addison’s disease (adrenal insufficiency)

Severe hyperkalemia, with plasma [K+] > 7mM, can be life-threatening, leading to asystolic cardiac arrest.

Acute management of hyperkalemia may involve insulin/glucose infusion to drive potassium (K+) back into cells.

Insulin is particularly important, although the mechanism is unclear; it may stimulate the Na-K-ATPase. Glucose is given with insulin to facilitate its entry into cells and provide energy.

Other hormones such as aldosterone and adrenaline stimulate the Na+-K+ pump, resulting in increased cellular K+ influx.

External K+ balance is primarily maintained by the kidney in a healthy individual.

K+ excretion in the stools is not under regulatory control, meaning that large amounts can be lost by extra-renal routes.

The maintenance of normal potassium (K+) homeostasis is becoming an increasingly important limiting factor in the therapy of cardiovascular disease (CVD).

Drugs like β-blockers and ACE inhibitors can increase serum [K+], thereby increasing the risk of hyperkalemia.

Loop diuretics, used to treat heart failure, can increase the risk of hypokalemia.

Human kidneys have evolved to conserve sodium (Na+) and excrete potassium (K+).

Sodium (Na+) and potassium (K+) are filtered freely at the glomeruli.

Plasma and glomerular filtrate (GF) have the same concentrations of sodium (Na+) and potassium (K+).

In a 24-hour period, the entire glomerular filtrate (~180 liters) contains approximately:

✿ 25 moles of sodium (Na+) (equivalent to 1.5 kg of NaCl)

✿ 0.7 moles of potassium (K+) (equivalent to 50 g of KCl)

Approximately 60-70% of sodium (Na+) and potassium (K+) are reabsorbed in the proximal convoluted tubule (PCT).

The fraction of sodium (Na+) and potassium (K+) reabsorbed in the PCT is approximately constant.

While the fraction remains constant, the absolute amount of sodium (Na+) and potassium (K+) reabsorbed in the PCT varies with glomerular filtration rate (GFR).

Greater than 90% of filtered potassium (K+) is reabsorbed in the proximal convoluted tubule (PCT) and the loop of Henle (LoH)

The excretion of potassium (K+) into urine during potassium overload is controlled by potassium (K+) secretion by principal cells of the late distal convoluted tubule (DCT) and the collecting duct (CD).

Potassium (K+) secretion in the DCT is determined by factors such as increased K+ intake and changes in blood pH. Alkalosis leads to increased excretion of K+, resulting in decreased serum [K+], while acute acidosis leads to decreased excretion of K+, resulting in increased serum [K+].

Potassium (K+) secretion in the DCT is achieved through:

✿ Activity of the Na-K-ATPase pump

✿ Electrochemical gradient

✿ Permeability of the luminal membrane channel

An increase in plasma potassium (K+) concentration increases K+ secretion in three ways:

✿ Slows exit from the basolateral membrane, leading to an increase in intracellular potassium concentration ([K+]i) and creating a cell-lumen concentration gradient.

✿ Increases the activity of the Na+/K+ ATPase, resulting in an increase in intracellular potassium concentration ([K+]i).

✿ Stimulates aldosterone secretion.

Aldosterone is the major regulator of potassium balance in the body.

Aldosterone acts to:

✿ Increase the activity of the Na+/K+ pump, resulting in increased potassium (K+) influx and intracellular potassium concentration ([K+]i), establishing a cell-lumen concentration gradient.

✿ Increase the number of epithelial sodium channels (ENaC), leading to increased sodium (Na+) reabsorption, reduced cell negativity, increased lumen negativity, and establishment of a voltage gradient.

✿ Redistribute ENaC from intracellular localization to the membrane.

✿Increase the permeability of the luminal membrane to potassium (K).

α-Intercalated cells of the late distal convoluted tubule (DCT) and collecting duct (CD) are active in the reabsorption of potassium (K+) during severe hypokalemia.

Coupling potassium (K+) excretion to distal flow rate could jeopardize potassium balance.

Glucocorticoid hormones (e.g., cortisol)

Sex hormones (androgens and estrogens)

Mineralocorticoid hormones (e.g., aldosterone)

Addison's disease is a condition characterized by primary adrenal insufficiency, which is rare compared to secondary adrenal insufficiency. It involves damage to the adrenal cortex, resulting in significantly decreased hormone production and numerous symptoms.

Addison's disease results in a deficiency of aldosterone, leading to the body secreting large amounts of sodium (Na+), low serum sodium levels, retention of potassium (K+), and hyperkalemia.

The usual treatment for Addison's disease involves corticosteroid (steroid) replacement therapy for life.

✿ Conn's Syndrome, also known as primary aldosteronism, is characterized by excess release of aldosterone due to an aldosterone-producing adenoma of the adrenal gland zona glomerulosa.

✿ These adenomas are typically less than 3cm in size, unilateral, and renin-unresponsive.

Hyperaldosteronism, characterized by excess release of aldosterone, can result from a variety of chronic diseases. Most commonly (50-60% of cases), it is due to Conn's syndrome, while the remaining 40-50% are due to bilateral adrenal hyperplasia.

In Conn's Syndrome, aldosterone is released in the absence of stimulation by angiotensin II.

In Conn's Syndrome, there is a significant increase in plasma aldosterone levels, leading to stimulation of sodium (Na+) reabsorption and potassium (K+) excretion by the kidneys. This results in the development of hypertension, increased fluid volume, and electrolyte imbalances such as hypokalemia, hypernatremia, and alkalosis.

Conn's Syndrome leads to hypertension due to increased blood pressure (bp) and sodium delivery to the macula densa, resulting in decreased release of renin. This creates a renin-independent cause of hypertension, making it very difficult to control.

Treatment options for Conn's Syndrome include surgical removal of the tumor-containing adrenal gland and controlling hypertension and hypokalemia with potassium-sparing agents such as spironolactone.