Etiology
Hyperkalemia most commonly occurs in people with renal impairment or those on drugs that alter the excretion of potassium. The main underlying causes of hyperkalemia include:
Increased intake of potassium in association with decreased renal excretion
Decreased cellular entry of potassium or increased exit of potassium from cells
A test-tube phenomenon leading to pseudohyperkalemia.
Key risk factors for hyperkalemia include:
Kidney dysfunction (particularly end-stage kidney disease where the estimated glomerular filtration rate [eGFR] drops below 30 mL/minute/1.73 m²), including people receiving dialysis who are fasting or have missed dialysis[1][2][12][13][14][15][16]
Use of renin-angiotensin-aldosterone system inhibitors (RAASi), which include ACE inhibitors, angiotensin-II receptor antagonists, and direct renin inhibitors; use of aldosterone antagonists (e.g., spironolactone, eplerenone); or use of trimethoprim (note that other drugs may also cause hyperkalemia - see pathophysiology section below)[1][2][17][18][19][20][21][22]
Liver disease[1]
Tissue breakdown (e.g., rhabdomyolysis, trauma, tumor lysis syndrome, and severe hypothermia)[2][24][25][26]
Distal renal tubule defects that affect potassium excretion.[16]
Pathophysiology
The kidney is primarily responsible for maintaining the total body potassium content. This is achieved by matching the potassium intake with potassium excretion. Levels of total body potassium are relatively well controlled in healthy individuals with normal renal function. The main causes of hyperkalemia include:
Increased intake of potassium in association with decreased renal excretion
Decreased cellular entry of potassium or increased exit of potassium from cells
A test-tube phenomenon leading to pseudohyperkalemia.
Increased intake of potassium
In the setting of normal renal function, it is rare for increased intake of potassium to result in hyperkalemia. However, it is not uncommon for hyperkalemia to occur even with normal intake of potassium when renal insufficiency is present, particularly in the patient with diabetes mellitus.[27] Life-threatening arrhythmias can also occur when excessive amounts of potassium are administered to individuals with renal failure and hypokalemia, due to transcellular redistribution with a time lag in blood sampling for ascertainment of potassium levels.
Decreased excretion of potassium
Acute or chronic renal insufficiency reduces the renal excretion of potassium. This most typically results in hyperkalemia when renal functional decline is accompanied by a high dietary intake of potassium, either from dietary foodstuffs or by way of potassium supplements. As glomerular filtration rate begins to decline below 60 mL/minute/1.73 m², the excretion of potassium begins to decline, particularly in the patient with diabetes or hyporeninemic hypoaldosteronism. As glomerular filtration rate falls below 30 mL/minute/1.73 m², significant diminution in potassium excretion occurs.
In renal tubular acidosis (RTA), especially type 4 RTA, the level of hyperkalemia may be disproportionately high compared with any decrease in glomerular filtration rate (i.e., level of potassium may be significantly elevated while renal function may be only mildly impaired). RTA should be considered as a cause for such laboratory findings if mineralocorticoid deficiency and/or drugs impairing either mineralocorticoid action or potassium transport have been ruled out as causes.
Several uncommon conditions can be associated with the development of hyperkalemia due to decreased potassium excretion. Increased sodium intake facilitates potassium excretion and, as such, low-sodium diets can significantly compromise the ability of the kidney to excrete potassium. Either a relative reduction in plasma aldosterone values (as occurs in people with diabetes) or an absolute reduction in plasma aldosterone values (as occurs in patients with Addison disease) can contribute to this process.
Other adrenal causes of hyperkalemia due to decreased potassium excretion include:
Pseudohypoaldosteronism (apparent state of renal tubular unresponsiveness or resistance to the actions of aldosterone; plasma aldosterone concentration, urinary aldosterone excretion, and plasma renin activity are usually elevated in pseudohypoaldosteronism, whereas plasma and urinary aldosterone excretion are low in hypoaldosteronism)
Congenital adrenal hyperplasia (salt-wasting state and/or aldosterone deficiency)
Lupus erythematosus (decreased tubular secretion of potassium relating to tubulointerstitial disease sometimes disproportionate to the level of renal function).
Several drugs can compromise the ability of the kidney to maintain potassium homeostasis. These include:
Potassium-sparing diuretics:[21][23][28][29][30][31]
Potassium-sparing diuretics include aldosterone antagonists (e.g., spironolactone, eplerenone), triamterene, and amiloride, which impact distal tubular and collecting duct potassium-handling mechanisms.[32] Hyperkalemia is dose-dependent and most significant when potassium is concurrently given, a potassium-enriched diet is being ingested, and some level of renal failure is present. Spironolactone is very long-acting and its residual effect on potassium homeostasis can remain for several days after it has been stopped.
Renin-angiotensin-aldosterone system inhibitors (RAASi):[33][34]
RAASi include ACE inhibitors, angiotensin-II receptor antagonists, and direct renin inhibitors. Treatment with a single drug in this class is associated with a low risk of hyperkalemia if there are no other risk factors present.[17] However, if the patient is taking multiple drugs in this class, receiving potassium supplements, has kidney dysfunction, or is volume depleted, the risk of hyperkalemia is significantly increased.[18][19][20] One trial that studied the effects of combination therapy with ACE inhibitors and angiotensin-II receptor antagonists in patients with diabetic nephropathy found that combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years) when compared with monotherapy (2.6 events per 100 person-years) (P <0.001).[19] The risk of developing hyperkalemia with certain other drugs may be increased when RAASi are taken concomitantly.
Trimethoprim or pentamidine:[22][35]
These drugs have amiloride-like properties and behave as potassium-sparing diuretics. The change in serum potassium is dose-dependent and greatest in older people, those with diabetes, and patients with renal insufficiency. Of note, even standard doses of the antibiotic combination trimethoprim/sulfamethoxazole, used commonly for urinary tract infections, can result in significant rises in serum potassium values. Both these drugs are commonly used in HIV-positive patients.
Nonsteroidal anti-inflammatory drugs (NSAIDs):[2][36]
These drugs decrease production of PGE2 and PGI2, which takes away two factors known to stimulate release of renin and thereby aldosterone. This phenomenon is to a degree dose-dependent, and is of more significance in those who already have hyporeninemic hypoaldosteronism, such as older people and those with diabetes. This process is accentuated if there is a concomitant decline in glomerular filtration rate with NSAIDs.
Hyperkalemia can occur with low doses, and within days of starting treatment. It occurs with both unfractionated heparin and low molecular weight heparin. The process relates to inhibition of adrenal synthesis of aldosterone and therein decreased renal potassium excretion. Typically, the increase in potassium is small (0.2 to 0.5 mEq/L [0.2 to 0.5 mmol/L]) but can be more substantial in patients with preexisting defects in potassium homeostasis.
Calcineurin inhibitors:[4][39][40]
Hyperkalemia can occur independent of nephrotoxic effects of calcineurin inhibitors (e.g., cyclosporine, tacrolimus) relating to renal tubule dysfunction and secondary hypoaldosteronism.
Decreased cellular entry of potassium or increased cellular exit
Decreased cellular entry of potassium is to be distinguished from increased cellular exit. The latter relates to the extracellular movement of fluid and potassium (solvent drag) in response to the difference in osmolality between the extracellular and intracellular compartments. A reduction in aldosterone effect or amount does not seem to have a significant effect on transcellular potassium shift.
Acid-base abnormalities, such as metabolic acidosis, can be marked by a shift of potassium from an intracellular to an extracellular location in exchange for hydrogen ions. This shift, which represents a form of buffering, occurs more so with the administration of substances such as arginine (rarely used to treat significant metabolic alkalosis) and hydrochloric acid.[41] Respiratory acid-base disturbances are associated with much smaller shifts of potassium than are metabolic disorders. Life-threatening arrhythmias can occur rapidly with arginine, relating to transcellular shifts of potassium, particularly in patients with hepatic disease who more poorly metabolize arginine and in patients with preexisting renal failure and/or diabetes mellitus.
Increased cellular exit occurs in response to osmotic gradients (hyperosmolality), such as is the case with hyperglycemia and following the administration of mannitol.[42] The rate and amount of mannitol given determines the extent of extracellular potassium flux.
Insulin and beta-2 agonists facilitate the cellular entry of potassium.[43] As such, a deficiency in insulin as well as blockade of beta-receptors (as occurs with noncardioselective beta-blockers) can be followed by a rise in serum potassium values.[44] Life-threatening arrhythmias are uncommon with noncardioselective beta-blockers because the associated increase in serum potassium values is both minor and transient.
Digoxin (digitalis) overdose, by inhibiting Na-K-ATPase, can cause dramatic and sometimes life-threatening increases in serum potassium.[45]
Hyperkalemia occurs in a small subset of patients after administration of succinylcholine, a depolarizing neuromuscular drug, and can be fatal.[46] In patients without neuromuscular disease, succinylcholine administration results in small, transient serum potassium increases of about 50 mEq/L (50 mmol/L). When skeletal muscle undergoes prolonged disuse or normal neural stimulation is absent, acetylcholine receptors upregulate, permitting a massive efflux of potassium from muscle cells with exposure to succinylcholine.
Increased cell turnover
Increased cell turnover can result in hyperkalemia. This can occur in the course of strenuous exercise, particularly when volume depletion and a resultant fall in glomerular filtration rate coexist. Increased cell damage, as occurs with rhabdomyolysis and tumor lysis syndrome, can also result in significant hyperkalemia, with or without a major fall in the level of renal function.[47][48]
Pseudohyperkalemia
Pseudohyperkalemia is a test-tube phenomenon wherein in vitro potassium values are variably in excess of those in vivo. This phenomenon is felt to be present when a serum potassium value exceeds a simultaneously obtained plasma value by >0.4 mEq/L (>0.4 mmol/L). Cell hemolysis in a sample placed in a test tube can falsely increase the serum potassium value. In addition, during the clotting process, potassium can be released from platelets and white blood cells, and when either of these cellular elements is present in abundance (platelets >500,000 or white blood cells >100,000 per mm³) the serum potassium can be falsely elevated.[49][50] This may also be seen with hereditary spherocytosis and familial pseudohyperkalemia wherein there is increased temperature-dependent release of potassium following sample collection.
Miscellaneous
Hyperkalemic periodic paralysis is a disorder associated with episodic muscle weakness in association with what may be sometimes very small increments in serum potassium values. This sensitivity to small changes in serum potassium values relates to specific cell membrane defects.[51] In reality, the use of the hyperkalemia qualifier for this form of periodic paralysis is a misnomer, because this disease is not associated with a readily determinable hyperkalemic serum potassium value. The hyperkalemia associated with ureterojejunostomy, an uncommonly performed surgical procedure, relates to loss of sodium chloride into jejunal fluid and absorption of potassium.
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