Aetiology
The main causes of hyperkalaemia are as follows:
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 so-called pseudohyperkalaemia.
Increased intake of potassium
In the setting of normal renal function it is rare for increased intake of potassium to result in hyperkalaemia. However, it is not uncommon for hyperkalaemia to occur even with normal intake of potassium when renal insufficiency is present, particularly in patients with diabetes mellitus.[2][3] Life-threatening arrhythmias can also occur when excessive amounts of potassium are administered to individuals with renal failure and hypokalaemia, 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 hyperkalaemia 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, the excretion of potassium begins to decline, particularly in patients with diabetes or hyporeninaemic hypoaldosteronism. As glomerular filtration rate falls below 30 mL/minute, significant diminution in potassium excretion occurs. In renal tubular acidosis (RTA), especially type 4 RTA, the level of hyperkalaemia 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 medications impairing either mineralocorticoid action or potassium transport have been ruled out as causes.
A number of uncommon conditions can be associated with the development of hyperkalaemia 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's disease) can contribute to this process. Other adrenal causes of hyperkalaemia 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); and lupus erythematosus (decreased tubular secretion of potassium relating to tubulointerstitial disease sometimes disproportionate to the level of renal function).
A number of drugs can compromise the ability of the kidney to maintain potassium homeostasis. These include:
Potassium-sparing diuretics, including aldosterone receptor antagonists (spironolactone, eplerenone), triamterene, and amiloride:[4] these drugs work on distal tubular and collecting duct potassium-handling mechanisms. Hyperkalaemia 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.
Non-steroidal anti-inflammatory drugs (NSAIDs):[5][6] these drugs decrease production of PGE2 and PGI2, which takes away 2 factors known to stimulate release of renin and thereby of aldosterone. This phenomenon is to a degree dose-dependent, and is of more significance in those who already have hyporeninaemic 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.
Trimethoprim or pentamidine:[7][8][9] these compounds have amiloride-like properties and behave as potassium-sparing diuretics. The change in serum potassium with these compounds 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.
ACE inhibitors, angiotensin-receptor blockers, direct renin inhibitors:[10][11][12] cause a state of hypoaldosteronism. Hyperkalaemia is more common with ACE inhibitor therapy, is dose-dependent, and is linked to the level of renal function. Typically, the increase in potassium is small (0.2-0.5 mmol/L [0.2-0.5 mEq/L]) but can be more substantial in patients with pre-existing defects in potassium homeostasis receiving potassium supplements and/or with volume depletion.
Heparin:[13][14] hyperkalaemia can occur with doses as low as 5000 units twice daily, and within days of starting treatment. It occurs with both unfractionated and low molecular weight heparin. The process relates to inhibition of adrenal synthesis of aldosterone and thereby decreased renal potassium excretion. Typically, the increase in potassium is small (0.2-0.5 mmol/L [0.2-0.5 mEq/L]) but can be more substantial in patients with pre-existing defects in potassium homeostasis.
Calcineurin inhibitors such as ciclosporin (cyclosporine) and tacrolimus:[15][16] hyperkalaemia can occur independent of nephrotoxic effects of these compounds relating to renal tubule dysfunction and secondary hypoaldosteronism.
Loop or thiazide-type diuretic therapy: by facilitating urine potassium losses, can mask tendencies to hyperkalaemia that might otherwise be apparent.
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 hydrochloride (rarely used to treat significant metabolic alkalosis) and hydrochloric acid.[17] Respiratory acid-base disturbances are associated with much smaller shifts of potassium than are metabolic disorders. Life-threatening arrhythmias can occur rapidly with arginine hydrochloride, relating to transcellular shifts of potassium, particularly in patients with hepatic disease who more poorly metabolise arginine, and in patients with pre-existing renal failure and/or diabetes mellitus.
Increased cellular exit occurs in response to osmotic gradients (hyperosmolality), as is the case with hyperglycaemia and following the administration of mannitol.[18] The rate (usually faster than 30 minutes) and amount of mannitol (usually >1 g/kg body weight) given determines the extent of extracellular potassium flux.
Insulin and beta-agonists facilitate the cellular entry of potassium.[19] As such, a deficiency in insulin as well as blockade of beta-receptors (as occurs with non-cardioselective beta-blocker therapy) can be followed by a rise in serum potassium values.[20] Life-threatening arrhythmias are uncommon with beta-blockers, since the associated increase in serum potassium values is both minor and transient.
Digitalis overdose, by inhibiting Na-K-ATPase, can cause dramatic and sometimes life-threatening increases in serum potassium.[21]
Hyperkalaemia occurs in a small subset of patients after administration of suxamethonium (succinylcholine), a depolarising neuromuscular drug, and can be fatal.[22] In patients without neuromuscular disease, suxamethonium (succinylcholine) administration results in small, transient serum potassium increases of about 50 mmol/L (50 mEq/L). When skeletal muscle undergoes prolonged disuse or normal neural stimulation is absent, acetylcholine receptors up-regulate, permitting a massive efflux of potassium from muscle cells with exposure to suxamethonium (succinylcholine).
Increased cell turnover
Increased cell turnover can result in hyperkalaemia. 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 tumour lysis syndrome, can also result in significant hyperkalaemia, with or without a major fall in the level of renal function.[23][24]
Pseudohyperkalaemia
Pseudohyperkalaemia 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 mmol/L (>0.4 mEq/L). Cell haemolysis 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 x 10⁹/L) the serum potassium can be falsely elevated.[25][26] This may also be seen with hereditary spherocytosis and familial pseudohyperkalaemia wherein there is increased temperature-dependent release of potassium following sample collection.
Miscellaneous
Hyperkalaemic 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.[27] In reality, however, the use of the hyperkalaemia qualifier for this form of periodic paralysis is a misnomer, since this disease is not associated with a readily determinable hyperkalaemic serum potassium value. The hyperkalaemia 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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