Hyperkalemia: Practice Essentials, Background, Pathophysiology

Potassium is the primary intracellular cation; 95-98% of the total body potassium is found in the intracellular space, primarily in muscle. Total body potassium stores amount to approximately 50 mEq/kg (3500 mEq in a 70-kg person).

Normal homeostatic mechanisms precisely maintain the serum potassium level within a narrow range (3.5-5.0 mEq/L). The primary mechanisms for maintaining this balance are the buffering of extracellular potassium against a large intracellular potassium pool (via the sodium-potassium pump), which provides minute-to-minute control, and urinary excretion of potassium, which determines total body potassium balance.

Potassium is obtained through the diet. Common potassium-rich foods include meats, beans, tomatoes, potatoes, and fruits such as bananas. Gastrointestinal (GI) absorption is complete, resulting in daily excess intake of about 1 mEq/kg (60-100 mEq).

Under normal conditions, approximately 90% of potassium excretion occurs in the urine, with less than 10% excreted through sweat or stool. Within the kidneys, potassium excretion occurs mostly in the principal cells of the cortical collecting duct (CCD). Urinary potassium excretion depends on adequate luminal sodium delivery to the distal convoluted tubule (DCT) and the CCD, as well as the effect of aldosterone and other adrenal corticosteroids with mineralocorticoid activity.

Renal factors in potassium homeostasis

Sodium reabsorption through epithelial sodium channels (ENaC) located on the apical membrane of cortical collecting tubule cells is driven by aldosterone and generates a negative electrical potential in the tubular lumen, driving the secretion of potassium at this site through the renal outer medullary potassium (ROMK) channels. Aldosterone also regulates sodium transport in the thick ascending limb of the loop of Henle, the DCT, and the connecting tubule.

A family of signaling molecules, the WNK (with no K [lysine]) kinases, plays a critical role in the regulation of sodium and potassium transport in the distal nephron. [4] The WNK kinases are suspected of playing a role in the pathogenesis of several forms of hypertension. [5, 6]

WNK1 and WNK4 regulate the expression and function of the NaCl cotransporter and ROMK in the distal tubule. Increased WNK4 activity results in decreased NaCl cotransporter expression, permitting greater delivery of sodium to the cortical collecting tubule, thus facilitating potassium secretion. Conversely, lesser WNK4 activity results in increased NaCl cotransporter expression, diminishing distal sodium delivery, thus limiting cortical collecting tubule potassium secretion. [7, 8]

Renal potassium excretion is increased by the following:

• Aldosterone
• WNK1 and WNK4
• High sodium delivery to the distal tubule (eg, diuretics)
• High urine flow (eg, osmotic diuresis)
• High serum potassium level
• Delivery of negatively charged ions to the distal tubule (eg, bicarbonate)

Renal potassium excretion is decreased by the following:

• Absence, or very low levels, of aldosterone
• WNK1 and WNK4 mutations
• Low sodium delivery to the distal tubule
• Low urine flow
• Low serum potassium level
• Kidney injury

Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion also is increased. Even in the absence of potassium intake, however, obligatory renal losses amount to 10-15 mEq/day. Thus, chronic losses occur in the absence of any ingested potassium.

In chronic kidney disease, renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate (GFR) decreases to less than 15-20 mL/min. Additionally, in the presence of kidney failure, the proportion of potassium excreted through the gut is thought to increase, though evidence for this compensatory mechanism has been elusive.

The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load. An excess of only 100-200 mEq will increase the serum potassium concentration by about 1 mEq/L. [9]

Potassium distribution and serum potassium levels

Potassium is predominantly an intracellular cation; thus, serum potassium levels do not always accurately reflect total body potassium stores. Serum potassium levels are determined by the shift of potassium between intracellular and extracellular fluid compartments, as well as by total-body potassium homeostasis.

Several factors regulate the distribution of potassium between the intracellular and extracellular spaces, including glucoregulatory hormones, adrenergic stimuli, and pH. Insulin enhances potassium entry into cells, whereas glucagon impairs it. Beta-adrenergic agonists enhance potassium entry into cells, whereas beta-blockers and alpha-adrenergic agonists inhibit it.

Alkalosis enhances potassium entry into cells. Acidosis causes a shift of potassium from intracellular space into extracellular space. Inorganic or mineral acid acidoses are more likely to cause a shift of potassium out of the cells than organic acidosis is.

In addition, an acute increase in osmolality, such as may result from hyperglycemia, causes potassium to exit from cells. Acute cell-tissue breakdown (eg, hemolysis or rhabdomyolysis) releases potassium into the extracellular space.

The 2 sets of regulatory factors—those that regulate total-body homeostasis and those that regulate distribution of potassium between intracellular and extracellular spaces—meld to create smooth control of potassium levels throughout the day. Thus, serum concentrations can remain stable even in the face of acute intake or loss of potassium.

For example, although a high-potassium meal might contain enough potassium to raise the serum potassium acutely to lethal levels if the potassium remained in the extracellular space, sodium-potassium–adenosine triphosphatase (Na+ -K+ -ATPase) rapidly takes up the potassium into cells, thus preventing the development of hyperkalemia. Adrenergic stimulation and insulin are important in maintaining the activity of Na+ -K+ -ATPase. The excess potassium then can be excreted by the kidneys, allowing serum potassium levels to return to normal.

Recent studies point toward a gastrointestinal-renal signal that is aldosterone-independent and causes enhanced renal potassium excretion after a meal. The mechanisms have not been fully determined. [10]

This integrated regulatory process is manifested in the diurnal rhythm for renal potassium excretion. The highest excretion occurs at midday, approximately 18 hours after peak potassium ingestion at the evening meal. [11]

Pathogenetic mechanisms

Hyperkalemia can result from any of the following:

• Excessive intake of potassium
• Decreased excretion of potassium
• A shift of potassium from the intracellular to the extracellular space

In many cases a combination of these factors is involved. For example, a person with a GFR of less than 45 mL/min who consistently eats large amounts of high-potassium foods and is taking a medication that blocks the rennin-angiotensin-aldosterone system is at very high risk for hyperkalemia due to limitations in renal excretion of potassium in the face of high intake.

A person with diabetes mellitus who has hyporeninemic hypoaldosteronism associated with diabetic nephropathy is at high risk for hyperkalemia due to a diminished ability to shift potassium into the intracellular space (insulin deficiency) and impaired renal excretion (aldosterone deficiency). A third circumstance is acute kidney injury from rhabdomyolysis or tumor lysis syndrome, in which hyperkalemia results from impaired renal excretion in addition to the release of large amounts of potassium from intracellular to extracellular fluid compartments.

Excessive intake

Excessive potassium intake alone is a very uncommon cause of hyperkalemia in anyone with an estimated GFR higher than 60 mL/min. The mechanisms for shifting potassium intracellularly and for renal excretion allow a person with normal potassium homeostatic mechanisms to ingest very high quantities of potassium. Even parenteral administration of as much as 60 mEq/hr for several hours creates only a minimal increase in serum potassium concentration in healthy individuals.

The most common source of increased potassium intake is intravenous (IV) or oral potassium supplementation. Packed red blood cells (PRBCs) may also carry high concentrations of potassium that can lead to hyperkalemia during PRBC transfusion. [12]

Decreased excretion

Decreased excretion of potassium, especially when coupled with excessive intake, is the most common cause of hyperkalemia. The most common causes of decreased renal potassium excretion include the following:

• Kidney failure (most common) [13]
• Medications that interfere with potassium excretion (eg, potassium-sparing diuretics, angiotensin-converting enzyme [ACE] inhibitors, [14, 15, 16, 17] and nonsteroidal anti-inflammatory drugs [NSAIDs])
• Reduced aldosterone production
• Impaired responsiveness of the distal tubule to the action of aldosterone (eg, type IV renal tubular acidosis observed with diabetes mellitus, sickle cell disease, or chronic partial urinary tract obstruction) [18, 19]
• Primary adrenal disease (eg, Addison disease or salt-wasting forms of congenital adrenal hyperplasia)
• Hyporeninemic hypoaldosteronism or renal tubular disease (pseudohypoaldosteronism I [20] or II)

Shift from intracellular to extracellular space

A number of factors can influence the shift of potassium from the intracellular to the extracellular space (see table below). By itself, this mechanism is a relatively uncommon cause of hyperkalemia, but it can exacerbate hyperkalemia produced by high intake or impaired renal excretion of potassium. A common scenario is that insulin deficiency or acute acidosis produces mild-to-moderate impairment of intracellular shifting of potassium.

Table. Selected Factors Affecting Plasma Potassium (Open Table in a new window)

Factor	Effect on Plasma K+	Mechanism
Aldosterone	Decrease	Increases sodium resorption, and increases K+ excretion
Insulin	Decrease	Stimulates K+ entry into cells by increasing sodium efflux (energy-dependent process)
Beta-adrenergic agents	Decrease	Increases skeletal muscle uptake of K+
Alpha-adrenergic agents	Increase	Impairs cellular K+ uptake
Acidosis (decreased pH)	Increase	Impairs cellular K+ uptake
Alkalosis (increased pH)	Decrease	Enhances cellular K+ uptake
Cell damage	Increase	Intracellular K+ release
Succinylcholine	Increase	Cell membrane depolarization

Clinical situations in which this mechanism is the major cause of hyperkalemia include the following:

• Hyperosmolality
• Tissue breakdown (eg, rhabdomyolysis, tumor lysis syndrome, or massive hemolysis)
• Propofol (“propofol infusion syndrome”) [21]
• Toxins (digitalis intoxication or fluoride intoxication)
• Succinylcholine (depolarizes the cell membrane and thus permits potassium to leave the cells [22, 23, 24] )
• Beta-adrenergic blockade
• Strenuous or prolonged exercise
• Malignant hyperthermia
• Hyperkalemic periodic paralysis

Hyperkalemia may also be caused by IV administration of epsilon aminocaproic acid (EACA), a synthetic amino acid. EACA has been found to cause hyperkalemia in studies conducted in dogs. The mechanism of action is presumed to be a structural similarity between EACA and arginine and lysine. These latter amino acids enter the muscle cell in exchange for potassium, thereby leading to an increase in extracellular potassium. [25, 26]

Cardiac and skeletal muscle effects

High levels of potassium cause abnormal heart and skeletal muscle function by lowering cell-resting action potential and preventing repolarization, leading to muscle paralysis. Classic electrocardiographic findings begin with tenting of the T wave, followed by lengthening and eventual disappearance of the P wave and widening of the QRS complex. [27] However, varying degrees of heart block are also common.

Just before the heart stops, the QRS and T wave merge to form a sinusoidal wave.