Because potassium (K⁺) is the major intracellular cation, discussion of disorders of K⁺ balance must take into consideration changes in the exchange of intra- and extracellular K⁺ stores. (Extracellular K⁺ constitutes <2% of total-body K⁺ content.) Insulin, β₂-adrenergic agonists, and alkalosis tend to promote K⁺ uptake by cells; acidosis, insulinopenia, or acute hyperosmolality (e.g., after treatment with mannitol or D₅₀W) promotes the efflux or reduced uptake of K⁺. A corollary is that tissue necrosis and the attendant release of K⁺ can cause severe hyperkalemia, particularly in the setting of acute kidney injury. Hyperkalemia due to rhabdomyolysis is thus particularly common, due to the enormous store of K⁺ in muscle; hyperkalemia may also be prominent in tumor lysis syndrome.

The kidney plays a dominant role in K⁺ excretion. Although K⁺ is transported along the entire nephron, it is the principal cells of the connecting segment and cortical collecting duct that play a dominant role in K⁺ excretion. Apical Na⁺ entry into principal cells via the amiloride-sensitive epithelial Na⁺ channel (ENaC) generates a lumen-negative potential difference, which drives passive K⁺ exit through apical K⁺ channels. This relationship is key to the bedside understanding of potassium disorders. For example, decreased distal delivery of Na⁺ tends to blunt the ability to excrete K⁺, leading to hyperkalemia. Abnormalities in the renin-angiotensin-aldosterone system (RAAS) can cause both hypo- and hyperkalemia; aldosterone has a major influence on potassium excretion, increasing the activity of ENaC channels and the basolateral Na+/K+-ATPase, thus amplifying the driving force for K⁺ secretion across the luminal membrane of principal cells.