Hypokalemia and hyperkalemia

1. Describe normal potassium balance.

Approximately 98% of total body potassium resides inside cells, making it the most abundant cation in the intracellular fluid (ICF). The total body stores approximately 3000 mEq or more (approximately 50 to 70 mEq/kg body weight) of K ⁺ , with the skeletal muscle cells providing the biggest storage site for intracellular K ⁺ . ICF concentration of potassium is approximately 140 mEq/L compared to only 4 to 5 mEq/L in the extracellular fluid (ECF).

2. Why is potassium balance important?

Since most of the total body potassium is intracellular, a large gradient exists between the ICF and ECF. This potassium gradient across the cell membrane is partially responsible for maintaining the potential difference across the cell membrane. This potential difference is critical for the function of cells, particularly excitable tissues like nerves and muscles.

3. What is the primary cellular mechanism that maintains potassium balance?

Most cells contain Na ⁺ -K ⁺ -ATPase pump on the cellular membrane which pumps 2 molecules of K ⁺ in and 3 molecules of Na ⁺ out of the cell. This pump is regulated by catecholamines, insulin, and the potassium level itself. The ability to rapidly shift potassium from the extracellular to the intracellular compartment is vital to prevent severe increases in the serum potassium from routine dietary ingestion.

4. What are the mechanisms for maintaining the internal potassium balance?

A typical Western diet ingests approximately 70 to 80 mEq of K ⁺ per day. Almost all the ingested potassium is absorbed by the intestine. Adjustments in the kidney potassium excretion to match potassium intake is the principal mechanism for maintaining potassium balance. Because the changes in the kidney excretion of potassium occur over several hours, the initial buffering of an increase in ECF potassium occurs by movement of potassium into skeletal muscle. With intact kidney function, only about 10% of dietary potassium is excreted in the feces.

5. Why don’t serum potassium levels go up when we eat a dietary potassium load (such as hamburger or soda)?

The ingestion of food causes release of insulin, which binds to its receptor on the cell membrane leading to the insertion of GLUT4 into the cell membrane (a glucose transporter). Similarly, insulin causes the membrane insertion and stimulation of Na ⁺ -K ⁺ -ATPase pump, leading to movement of potassium into the cell, preventing a rise in the serum potassium.

6. What are the “feedback control” and “feed-forward” effects in potassium balance?

Elevation of plasma potassium causes the activation of mechanisms (insulin and aldosterone effects) that lower plasma potassium. This is an example of a negative feedback system where potassium excretion increases in response to increases in the plasma potassium level.

On the other hand, a feed-forward system responds to potassium intake in a manner that is independent of changes in the systemic plasma potassium level. In sheep, intake of potassium-rich foods triggers a significant increase in urinary potassium excretion without an increase in the serum potassium. The signal between the gastrointestinal (GI) tract and the kidney potassium handling that is responsible for this feed-forward control is unknown.

7. How do catecholamines affect internal potassium balance?

β2 adrenergic stimulation by catecholamines leads to increased Na ⁺ -K ⁺ -ATPase pump activity through a cyclic adenosine monophosphate (AMP) and protein kinase A dependent pathway primarily in the skeletal muscle leading to increased cellular uptake. This physiological effect is the basis for using β2 agonists like albuterol in the treatment of hyperkalemia.

8. What role do skeletal muscle cells play in internal balance of potassium during exercise?

In addition to taking part in cellular uptake of potassium under the influence of insulin, skeletal muscle cells also participate in the changes of ECF potassium that occur with exercise. Exercise increases ECF potassium, which limits muscle excitability and contractility leading to fatigue. Increased ECF potassium also causes vasodilation, increasing blood flow to exercising muscle. Exercise causes β2 adrenergic mediated stimulation of Na ⁺ -K ⁺ -ATPase pump that shifts potassium back into the cells.

9. What factors can cause hypokalemia by shifting potassium into cells?

Hypokalemia due to intracellular shift of K ⁺ primarily occurs due to insulin, β2 adrenergic stimulation, α-adrenergic antagonists, and metabolic alkalosis.

10. What factors can cause hyperkalemia by shifting potassium out of cells?

Hyperkalemia due to shift of potassium from the cells can occur in metabolic acidosis, exercise, insulin deficiency, β-adrenergic blockade, and α-adrenergic stimulation, as well as conditions like hyperglycemia that increase serum osmolality. Hyperglycemia, which pulls water from the cells, can lead to a solvent drag that also shifts potassium from cells.

11. Describe kidney potassium handling?

Two-thirds of the potassium that is filtered by the glomerulus is passively reabsorbed with sodium and water in the proximal tubule. After further reabsorption in the ascending limb of loop of Henle via the Na ⁺ -K ⁺ -2Cl ⁻ cotransporter, only about 10% of the filtered load reaches the distal nephron. The ability to secrete potassium begins in the early distal convoluted tubule and progressively increases along the distal nephron into the cortical collecting duct. The rate of potassium secretion by the distal nephron depends on the physiological need. The principal cells in the initial collecting duct and the cortical collecting duct are responsible for potassium secretion through the renal outer medullary potassium (ROMK) and large conductance potassium (BK) channels. In states of potassium depletion, reabsorption of potassium occurs in the collecting duct via the apical H ⁺ -K ⁺ ATPase on α-intercalated cells.

12. What factors determine kidney potassium excretion?

The two principal factors that determine the potassium secretion in the distal nephron are mineralocorticoid activity (aldosterone) and distal delivery of sodium and water (urine flow).