Hyperkalemia and hypokalemia

Overview of potassium homeostasis

The kidney is the most important organ for regulating K ⁺ homeostasis. It maintains total body K ⁺ content by matching excretion with intake. Hyperkalemia is rare in healthy individuals because of the kidneys’ ability to readily filter K ⁺ . With preserved renal function, most patients can consume up to 400 mEq per day or more of K ⁺ without developing clinically significant hyperkalemia. More than 90% of the filtered K ⁺ is reabsorbed in the proximal tubule and ascending limb of the loop of Henle. This reabsorption is primarily mediated by changes in sodium concentration, activity of the sodium-potassium-chloride (Na ⁺ -K ⁺ -2Cl ⁻ ) cotransporter, and activity of the sodium/potassium–adenosine triphosphatase pump (Na ⁺ -K ⁺ -ATPase).

The mineralocorticoid aldosterone plays an important role in renal K ⁺ handling. It increases intracellular K ⁺ concentration by stimulating the Na ⁺ -K ⁺ -ATPase in the basolateral membrane of proximal tubule cells. In the thick ascending limb, it promotes K ⁺ secretion by stimulating sodium reabsorption across the luminal membrane. Overall, when hyperkalemia is present, aldosterone promotes renal K ⁺ secretion in order to normalize serum K ⁺ concentration. In addition to hyperkalemia, the release of aldosterone is stimulated by activation of the renin–angiotensin–aldosterone system (RAAS). Medications and disease states that interfere with the normal functioning of this pathway can significantly alter K ⁺ levels.

Approximately 2% of total body K ⁺ is in the extracellular fluid, and 98% of K ⁺ is in the intracellular compartment. Because the changes in renal K ⁺ excretion described earlier can take hours to occur, the body has developed several physiologic mechanisms to quickly shift K ⁺ across cell membranes in order to prevent life-threatening deviations outside of the normal range. Under normal conditions, transcellular K ⁺ shifts are primarily affected by insulin, catecholamines, tonicity, and acid-base disorders. ^,

By increasing activity of the Na ⁺ -K ⁺ -ATPase, insulin decreases serum K ⁺ by shifting it intracellularly. Increased K ⁺ intake causes catecholamine secretion and beta-2-receptor stimulation. Like insulin, this sympathetic stimulation results in increased activity of the Na ⁺ -K ⁺ -ATPase and enhanced K ⁺ uptake into skeletal muscle cells. Extracellular hypertonicity creates an osmotic gradient that promotes K ⁺ efflux out of cells, increasing serum levels. Nongap metabolic acidosis causes a K ⁺ shift into the extracellular compartment, likely mediated by the effects of acidosis on transporters that regulate skeletal muscle cell pH. The changes in K ⁺ dynamics in response to high anion gap metabolic acidosis and respiratory acid-base disorders are minimal.

Hyperkalemia

Although no consistent definition exists, hyperkalemia is present when serum K ⁺ >5.0 mEq/L. The severity of hyperkalemia can be further classified as mild (K ⁺ = 5.1–5.5 mEq/L), moderate (K ⁺ = 5.6–6.0 mEq/L), or severe (K ⁺ >6.0 mEq/L). Understanding the characteristics of the laboratory sampling site is important for ensuring an accurate diagnosis. Although serum, plasma, and whole blood are generally acceptable specimens for quantifying K ⁺ levels, the composition of the sample site will affect the reported concentration. For example, pseudohyperkalemia describes an in vitro process by which measured serum K ⁺ is elevated relative to plasma concentrations. This typically occurs in the setting of thrombocytosis as platelets release K ⁺ during the clotting process, and plasma samples are devoid of platelets. In reverse pseudohyperkalemia, the in vitro concentration of plasma K ⁺ exceeds that of serum. This can occur in the setting of significant leukocytosis, with cell lysis causing a release of intracellular K ⁺ . Both entities are preanalytical phenomena and do not represent clinically significant hyperkalemia.

True hyperkalemia occurs as a result of increased extracellular K ⁺ or decreased K ⁺ excretion ( Table 16.1 ). Major risk factors for hyperkalemia include renal failure, diabetes mellitus, and the use of medications that impair renal K ⁺ excretion. ^, Hyperkalemia rarely occurs in patients with normal kidney function, and both acute and chronic renal insufficiency decrease K ⁺ excretion. When the glomerular filtration rate (GFR) is <15 mL/min/1.73 m ² , even small increases in K ⁺ intake can cause severe hyperkalemia. In patients with chronic kidney disease, the risk of hyperkalemia correlates strongly with estimated GFR (eGFR). The likelihood of developing hyperkalemia approximately doubles when eGFR <15 mL/min/1.73 m ² . Patients with diabetes mellitus have a higher incidence of hyperkalemia than the general population. Contributing factors include insulin deficiency and reduced tubular secretion of K ⁺ because of hyporeninemic hypoaldosteronism.

The administration of medications that impair the RAAS is a major risk factor for elevated serum K ⁺ . Direct renin inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can all decrease renal K ⁺ excretion. ^, Beta-2-receptor blockers and nonsteroidal antiinflammatory drugs (NSAIDs) impair renin release. Heparin and ketoconazole decrease aldosterone synthesis. ^, For most patients, RAAS blockade with only a single agent confers a low risk of hyperkalemia; however, the risk increases in the presence of other factors such as male sex, high baseline K ⁺ , low eGFR, diabetes mellitus, heart failure, and coadministration of potassium-sparing diuretics.

Pentamidine and trimethoprim can contribute to hyperkalemia by blocking the epithelial sodium channel (ENaC) in the distal nephron. Compared with other antibiotics, trimethoprim administration is associated with an increased risk of acute kidney injury and hyperkalemia in patients aged 65 and over. Calcineurin inhibitors cause downregulation of mineralocorticoid expression, leading to decreased mineralocorticoid function and aldosterone resistance.

Hyperkalemia can develop as a result of transcellular K ⁺ dynamics, specifically the result of the release of intracellular K ⁺ or the prevention of extracellular-to-intracellular K ⁺ shifts. Given that K ⁺ is primarily located in the intracellular compartment, significant cell lysis from tissue injury, hemolysis, rhabdomyolysis, or tumor lysis can increase serum K ⁺ levels. Succinylcholine is a depolarizing muscle relaxant that promotes K ⁺ efflux from skeletal muscle cells. The hyperkalemic response can be severe if given in the setting of burns, trauma, denervation, or prolonged immobility. Administration of the positively charged amino acids l -lysine and l -arginine promote a transcellular shift of K ⁺ to the extracellular component to maintain electroneutrality. Epsilon-aminocaproic acid is a lysine structural analogue and can produce hyperkalemia via a similar mechanism. Familial hyperkalemic periodic paralysis is a rare autosomal dominant genetic disorder that results from a mutation in sodium channel function.