Pathogenesis of Acute and Chronic Hyperkalemia

Hyperkalemia occurs when there is a defect in one or more of the mechanisms that maintain homeostasis1,2

Fairly uncommon causes of hyperkalemia, or elevated serum potassium (K+ >5.0 mEq/L), include increased K+ load and intracellular-to-extracellular shifts.2,3 Increased input can result from a number of different factors, including diet, salt substitutes, supplements, blood transfusions, hemolysis, GI bleeding, crush injuries, and cell catabolism.2

Abnormal distribution of K+ between intracellular and extracellular levels leads to a failure of electrical signals passing through cell membranes (cell depolarization).3 This is often caused by acidosis, hypertonicity, insulin deficiency, aldosterone deficiency, tissue damage, excess exercise, digitalis (impairs K+ uptake by cells blocking the sodium pump), or the use of β-blockers.2-4

The more common cause of hyperkalemia is decreased renal excretion of K+.3 This defect can be due to a number of different reasons:

  • Acute renal failure or decreasing renal function as seen with CKD complications
  • Impairment of the renin-angiotensin-aldosterone system (RAAS) as a result of aging, certain medical conditions, or commonly used medications in cardiovascular and kidney disease.2 (See more on how medications can increase the risk of hyperkalemia)

Dietary potassium intake may cause a transient disequilibrium and result in elevated serum potassium levels

Severe hyperkalemia from oral potassium intake is extremely rare if kidney function is normal, because the intake of potassium from food sources is usually handled through the normal homeostatic processes. However, if these homeostatic mechanisms are disrupted by renal insufficiency, insulin deficiency, or other factors, or if large amounts of potassium are ingested over a short period of time, these homeostatic mechanisms may break down.3,5

Some common foods have very high potassium content and should be limited. In particular, potassium chloride and other potassium compounds, which are used by the general public as salt substitutes or as muscle-building supplements, should be avoided.2,3 (See a list of potassium-rich foods)

The risk for hyperkalemia is higher among patients with renal impairment at all stages of kidney disease6

In patients with CKD, the decline in kidney function reduces the maximal capacity for K+ secretion and excretion.2,7

With impaired kidney function, the amount of K+ excreted through urine becomes compromised and decreases to less than 90%.2 This appears to be a product of an inadequate number of nephrons that manifest as decreasing glomerular filtration rate (GFR).8 As the GFR in these patients decreases, the body's ability to regulate K+ or maintain K+ homeostasis is further diminished, raising the risk for hyperkalemia.6

In addition to reduced GFR, a deficiency in aldosterone may contribute to the pathogenesis of hyperkalemia, as observed in patients with hypoaldosteronism with chronic renal insufficiency.9

Additional mechanisms that affect the intracellular/extracellular balance, such as acidosis and hyperosmolarity, can be increased in CKD, further causing an increase in serum K+.2,10

As urinary excretion of potassium decreases, the colon assumes an ancillary but limited role by increasing potassium excretion2,7

The colon, in addition to the kidneys, plays a critical role in K+ regulation. As part of an adaptive response to the deficit in kidney function, a net K+ influx is mediated by the sodium-potassium ATPase and the sodium-potassium-chloride cotransporters. This results in a compensatory increase in K+ secretion by the colon. This is mainly through upregulation of Big Potassium channels. These channels pump excess K+ from the epithelial cells lining the colon into the colonic lumen.2,7 (Watch video now)

This results in the colon compensating for 30%-50% of the increased serum potassium. However, as the compensating mechanisms of the colon reach their limits, serum potassium will continue to be elevated.2

Other disorders that cause hyperkalemia

K+ elevation most often occurs in patients with CKD or other illness that reduce K+ excretion by the kidneys.11


Acute vs recurrent hyperkalemia

Hyperkalemia can present as an isolated acute episode or as recurring hyperkalemic events.4,6 While acute hyperkalemia does occur in non-CKD patients, recurrent hyperkalemia also poses a chronic threat in CKD patients.

This table points to the main differences between acute and recurrent hyperkalemia; chiefly that acute hyperkalemia is a singular event caused by an abnormal net release of potassium from cells, whereas hyperkalemia may be considered recurrent if more than one event occurs per year caused by the impairment of the processes that promote potassium excretion.