For the full versions of these articles see bmj.com CLINICAL REVIEW Hyperkalaemia Moffat J Nyirenda,1 Justin I Tang,1 Paul L Padfield,2 Jonathan R Seckl1 1Endocrinology Unit, Centre for Hyperkalaemia is defined as serum potassium concen- SUMMARY POINTS Cardiovascular Science, Queen’s tration greater than 5.5 mmol/l. Its prevalence in the Medical Research Institute, Hyperkalaemia is usually caused by a combination of University of Edinburgh, Edinburgh general population is unknown, but it is thought to occur factors, but renal failure and drugs are often implicated 1 EH16 4TJ in 1-10% of patients admitted to hospital. The rate of Increased use of drugs that interact with the renin- 2Metabolic Unit, Western General morbidity and mortality associated with hyperkalaemia angiotensin-aldosterone system has caused the Hospital, Lothian University has risen greatly with the use of drugs that target the prevalence of hyperkalaemia to rise Hospitals NHS Trust, Edinburgh renin-angiotensin system, and since publication 10 years Correspondence to: M Nyirenda Hyperkalaemia can cause life threatening cardiac [email protected] ago of a randomised trial that showed that adding an arrhythmias and should be urgently managed aldosterone receptor antagonist to usual treatment for ECG changes correlate poorly with the degree of potassium Cite this as: BMJ 2009;339:b4114 congestive failure improved outcomes.2-5 disturbance doi: 10.1136/bmj.b4114 Potassium is the most abundant cation in the human body and has key roles in the excitatory properties range from 40 mmol to 200 mmol per day, potassium needed for conduction of nerve impulses and muscle levels in serum remain within the relatively narrow contraction. Ninety eight per cent of the body’s potas- normal range. Derangements in potassium regulation, sium is in the intracellular fluid (concentration about and resultant changes in serum potassium concentra- 140 mmol/l), with only 2% in extracellular fluid (3.8-5.0 tion, may alter membrane excitability. Disorders of mmol/l). A complex interplay of regulatory mechanisms plasma potassium can therefore have profound effects is needed to maintain normal potassium balance, which on nerve, muscle, and cardiac function. involves the transfer of potassium between the extra- cellular and intracellular compartments (fig 1). In the What are the common causes of hyperkalaemia? long term potassium homoeostasis is mainly governed Multiple factors are often involved in the pathogen- by regulation of renal potassium excretion, notably by esis of hyperkalaemia, which commonly results from the actions of aldosterone (fig 2). These mechanisms decreased potassium excretion or increased release of ensure that although total daily potassium intake could potassium from cells.6 Hyperkalaemia can be spurious, and this possibility should be excluded first, except in severe cases when immediate treatment is needed. ICF ECF Spurious hyperkalaemia [K+] = 140 [K+] = 4 Spurious hyperkalaemia (also called pseudohyperka- laemia) occurs when the reported laboratory potassium Insulin and β agonists shift potassium into cells values do not reflect actual in vivo concentrations— Nucleus K+ usually because platelets, leucocytes, or erythrocytes 2K+ have released intracellular potassium in vitro. It can ATPase Acidosis, hyperosmolarity, cell lysis shift potassium be excluded by sending a new sample for analysis or out of cells by simultaneously measuring potassium in plasma and 3Na+ serum; serum potassium concentration is usually 0.2– 0.4 mmol/l higher than that in plasma, owing to release during normal clotting. Box 1 lists common causes of spurious hyperkalaemia. Fig 1 | Schematic representation of regulation of transcellular potassium movement. Cellular potassium concentration is controlled by an active uptake mechanism regulated by Na-K-ATPase Hyperkalaemia due to increased potassium intake and a passive leak mechanism driven by the electrochemical gradient favouring potassium exit Excessive dietary intake of potassium is an uncommon from the cell. The rate of leak is dependent on the permeability of the potassium channels in the cause of hyperkalaemia, unless concurrent decreased cell membrane. Insulin and β2 adrenergic agonists (acting via cyclic AMP) promote potassium uptake into cells by stimulating the Na-K-ATPase pump. Insulin deficiency and β blockers excretion is a factor. High potassium intake should be increase potassium movement out of cells leading to hyperkalaemia. Acidosis, hyperosmolarity, avoided in patients with compromised renal function. or cell lysis also cause potassium to leave cells and can cause hyperkalaemia. ECF=extracelluar Box 2 lists foods rich in potassium. Hyperkalaemia fluid; ICF=intracellular fluid can also occur with blood transfusion (due to release BMJ | 31 OCTOBER 2009 | VOLUme 339 1019 CLINICAL REVIEW Hyperkalaemia caused by shift of potassium out of cells Blood Aldosterone Lumen Several endogenous and exogenous factors can affect transfer of potassium between the extracellular and intracellular fluid to raise the concentration in serum. However, this mechanism is rarely the sole cause of Gene transcriptionan severe hyperkalaemia, except when excessive release in nucleusuc of intracellular potassium occurs with tissue injury or necrosis—for example, in rhabdomyolysis, tumour lysis, and severe burns. Box 3 shows causes of hyperkalaemia 3Na+ due to potassium redistribution. ATPase ENaC Na+ 2K+ Hyperkalaemia caused by reduced excretion of potassium The kidneys are the main route of potassium elimination, and renal failure is the major cause of hyperkalaemia, K+ K+ K+ accounting for up to 75% of cases of severe hyperkalae- 1 H+ mia. In patients with chronic kidney disease, the capac- ity to excrete potassium is reasonably well maintained until renal failure is advanced (glomerular filtration rate <15-20 ml/min); until then hyperkalaemia is not usually seen unless intake of potassium is high or the patient is Fig 2 | Schematic representation of mineralocorticoid action in target cell in renal cortical collecting duct. On entering the cell, aldosterone binds to the mineralocorticoid receptors taking a drug that promotes hyperkalaemia. (MR). The ligand-receptor complex translocates to the nucleus and binds to hormone response Damage to the juxtaglomerular apparatus with result- elements, increasing transcription of specific genes, which in turn signal to increase activities ing deficit in renin production can cause hyporeninaemic of apical sodium channels (ENaC) and the basolateral Na-K-ATPase. This leads to increased hypoaldosteronism, which can also cause hyperkalaemia intracellular potassium concentration and a greater diffusion gradient for potassium to diffuse in the absence of severe renal failure. Hyporeninaemic into the lumen. Increased uptake of sodium leads to more negative lumen charge, facilitating hypoaldosteronism is also known as type 4 renal tubular the diffusion of potassium into the lumen. Disorders of aldosterone action are common causes acidosis because it is often, but not always, associated of hyperkalaemia. Renal potassium excretion is also affected by urine flow rate and delivery of with mild to moderate metabolic acidosis with a nor- sodium to the distal nephron mal anion gap. Diabetic nephropathy is the most com- of potassium from haemolysis), when intravenous mon underlying cause. Hypoaldosteronism can also be potassium is administered too rapidly in treatment of caused by primary disorders of the adrenal gland (such hypokalaemia, or when total parenteral nutrition con- as Addison’s disease or congenital steroidogenic enzyme tains high concentrations of potassium. defects, most commonly 21 hydroxylase deficiency) or by reduced mineralocorticoid activity due to resistance to the action of aldosterone action in the kidney. The lat- Box 1 | Causes of spurious hyperkalaemia ter problem is often seen in sickle cell anaemia, systemic Laboratory error lupus erythematosus, amyloidosis, and obstructive neph- Delayed analysis ropathy or with use of potassium sparing diuretics. In Blood collected from vein into which potassium is infused rare cases, it is caused by mutations of the gene encoding Excessive tourniquet or repeated fist clenching the mineralocorticoid receptor or its major downstream Haemolysis via small needle or traumatic venepuncture targets, including the epithelial sodium channel ENaC. Prolonged storage of blood In general, an abnormality in mineralocorticoid Severe leucocytosis or thrombocytosis level by itself does not produce hyperkaelemia if Uncommon genetic disorders (familial sufficient amount of sodium is delivered to the dis- pseudohyperkalaemia) tal nephron. Thus, patients with Addison’s disease do not usually exhibit hyperkalaemia if they have adequate salt intake; it is only when sodium intake is Box 2 | Foods with high potassium content restricted or they otherwise become volume depleted Salt substitutes that hyperkalaemia develops. Disturbances of urinary Figs flow rate or delivery of sodium to the distal neph- Molasses ron are therefore also important in the pathogenesis Seaweed of hyperkalaemia. These defects can be intrinsic or Chocolates (more commonly) caused by drugs (box 3, box 4). Bran cereal, wheat germ Vegetables (such as spinach, tomatoes, mushrooms, Which drugs cause hyperkalaemia? carrots, potatoes, broccoli, lima beans, cauliflower) Drugs can interfere with potassium homoeostasis by Dried fruit, nuts, and seeds promoting transcelluar potassium shift or by impair- Fruits (such as banana,