Approach Considerations
Hypokalemia is defined as a condition in which the serum potassium level is less than 3.5 mEq/L (3.5 mmol/L). [50] By far the most common causes of hypokalemia are potassium losses caused by diuretics or gastrointestinal disorders.
In most cases, the cause of hypokalemia is apparent from the history and physical examination. However, measurement of urine potassium is of vital importance because it establishes the pathophysiologic mechanism behind hypokalemia and, thus, aids in formulating the differential diagnosis. A serum magnesium assay is also important in the differential diagnosis, as well as in therapy, and is therefore performed as a first-line test.
Perform an electrocardiogram (ECG) to determine whether the hypokalemia is affecting cardiac function or to detect digoxin toxicity. The ECG may show atrial or ventricular tachyarrhythmias, decreased amplitude of the P wave, or appearance of a U wave.
Depending on history, physical examination findings, clinical impressions, and urine potassium results, the following tests may be appropriate. They should not be first-line tests, however, unless the clinical index of suspicion for the disorder is high:
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Drug screen in urine and/or serum for diuretics, amphetamines, and other sympathomimetic stimulants
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Serum renin, aldosterone, and cortisol
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24-hour urine aldosterone, cortisol, sodium, and potassium
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Pituitary imaging to evaluate for Cushing syndrome
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Adrenal imaging to evaluate for adenoma
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Evaluation for renal artery stenosis
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Enzyme assays for 17-beta hydroxylase deficiency
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Thyroid function studies in patients with tachycardia, especially Asians [2]
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Serum anion gap (eg, to detect toluene toxicity)
Simultaneous serum insulin and C-peptide tests can detect covert insulin use, which may occur in Münchhausen or Münchhausen-by-proxy syndrome. An elevated serum insulin level without an appropriately elevated C-peptide level suggests exogenous insulin administration.
Urine Potassium and Other Electrolytes
Urine potassium
A urine potassium assay establishes the pathophysiologic mechanism of hypokalemia. A spot urine potassium measurement is, for obvious reasons, the easiest and most commonly obtained test. Low urine potassium (< 20 mEq/L) suggests gastrointestinal loss, poor intake, or a shift of extracellular potassium into intracellular space. High urine potassium (>40 mEq/L) suggests renal loss.
If the urine potassium level is less than 20 mEq/L, question the patient regarding the following:
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Diarrhea and use of laxatives
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Diet or total parenteral nutrition (TPN) contents
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The use of insulin, excessive bicarbonate supplements, and episodic weakness
If the urine potassium level is higher than 40 mEq/L, examine the patient's medication list and question the patient regarding the use of diuretics.
Urine potassium in 24 hours
While more cumbersome to obtain, a 24-hour urine measurement of potassium excretion yields more precise data on how much potassium is being lost through renal excretion. Because the kidneys can conserve up to approximately 10-15 mEq of potassium per day, a value of less than 20 mEq on a 24-hour urine specimen suggests appropriate renal conservation of potassium, while values above that indicate some degree of renal wasting. To ensure that a full and accurate 24-hour urine sample has been collected, urine creatinine should be measured simultaneously.
Urine sodium
A spot urine sodium and osmolality test obtained simultaneously with a spot urine potassium test can help to refine the interpretation of the urine potassium level. A low urine sodium level (< 20 mEq/L) with a high urine potassium level suggests the presence of secondary hyperaldosteronism.
Urine sodium:chloride ratio
Wu et al reported that urinary levels of sodium (Na+) and chloride (Cl-) were high and coupled (Na+: Cl- ratio ∼1) in patients with renal tubular disorders and those using diuretics, but urinary Na+: Cl- ratios were skewed or uncoupled in patients with anorexia/bulimia nervosa (5.0 ± 2.2) and in patients abusing laxatives (0.4 ± 0.2). [51]
Urine Osmolality
If the urine osmolality is high (>700 mOsm/kg), then the absolute value of the urine potassium concentration can be misleading and can suggest that the kidneys are wasting potassium. For example, suppose the serum potassium level is 3 mEq/L and the urine potassium level is 60 mEq/L. The high urine potassium level would suggest renal potassium loss. However, the final concentration of potassium in the urine is dependent not only on the quantity of potassium secreted in response to sodium reabsorption, but also on the concentration of the urine.
In the above example, if urine osmolality is 300 mOsm/kg (ie, not concentrated relative to serum), then a measured urine potassium of 60 mEq/L indeed suggests renal potassium loss.
However, if the urine osmolality is 1200 mOsm/kg (ie, concentrated 4-fold relative to serum), then the 60-mEq/L potassium concentration would, in the absence of urinary concentration due to water reabsorption, be only 15 mEq/L (ie, very low). The conclusion would then be that the kidneys are not responsible for the low serum potassium.
Trans-Tubular Potassium Gradient
The TTKG was developed to account for the potentially confounding effect of urine concentration on the interpretation of the urine potassium concentration. [52, 53] In effect, the TTKG represents a back-calculation of what the serum-to–tubular fluid ratio of potassium would be at the level of the cortical collecting tubule, where potassium is secreted before urine concentration has occurred.
This test is performed using the following equation:
TTKG = Urine potassium x serum osmolality/Serum potassium x urine osmolality
A TTKG value of less than 3 suggests that the kidney is not wasting excessive potassium, while a value of greater than 7 suggests a significant renal loss. This test cannot be applied when the urine osmolality is less than the serum osmolality. Potassium excretion at the distal nephron is highly dependent on sodium delivery to that site. Therefore, low urine potassium in the presence of very low urine sodium (< 25 mEq/L) does not allow the clinician to exclude the possibility of a potassium-wasting syndrome.
Measurement of the TTKG was initially considered superior to measurement of urine potassium alone for assessing the contribution of renal excretion to potassium levels. However, it is important to recognize that the TTKG is valid for this purpose only if (1) the urine osmolality is greater than the serum osmolality—that is, the urine is concentrated relative to the serum—and (2) the urine sodium is greater than 20 mEq/L—that is, distal delivery of sodium is adequate for potassium excretion.
Furthermore, recent evidence suggesting that urea recycling may influence potassium secretion has cast some doubt on the utility of the TTKG. [54] One assumption inherent in the calculation of the TTKG is that the absorption of osmoles distal to the cortical collecting duct is negligible. If further studies suggest that urea transport can influence potassium handling, this test may have to be abandoned.
Metabolic Profile
Obtain a basic metabolic profile. Measure electrolytes, blood urea nitrogen (BUN), and creatinine. Including the glucose, calcium, and/or phosphorus level is indicated if coexistent electrolyte disturbances are suspected. Consider a digoxin level if the patient is on a digitalis preparation, as hypokalemia can potentiate digitalis-induced arrhythmias.
Serum sodium
A low serum sodium level suggests thiazide diuretic use or marked volume depletion from gastrointestinal losses. A high serum sodium might suggest that nephrogenic diabetes insipidus has occurred secondary to hypokalemia. This could indicate that the hypokalemia is a long-standing problem. A high serum sodium level also may suggest the presence of primary hyperaldosteronism, especially if hypertension also is present.
Serum bicarbonate
A low serum bicarbonate level may suggest renal tubular acidosis, diarrhea, or the use of carbonic anhydrase inhibitors (eg, acetazolamide, topiramate). A high serum bicarbonate level is consistent with either primary or secondary hyperaldosteronism. Causes of secondary hyperaldosteronism could be exogenous prednisone therapy, vomiting, or the use of thiazide or loop diuretics. A high serum bicarbonate level is also consistent with the presence of Bartter, Gitelman, or Liddle syndrome.
Other findings
The glucose level may be elevated; hyperglycemia may suggest that the hypokalemia has been of sufficient severity and duration to impair glucose tolerance.
Creatine kinase may be elevated in the occasional patient whose hypokalemia is of sufficient severity to produce not only muscle weakness but also frank rhabdomyolysis. This most often occurs in the setting of alcoholism, in which total body potassium stores may be quite low because of prolonged periods of poor intake. Severe rhabdomyolysis can lead to renal failure and subsequent severe hyperkalemia.
The magnesium level may be low, because severe hypokalemia often is associated with significant magnesium losses. In such cases, the potassium level cannot be corrected until the hypomagnesemia has been corrected.
Acid-Base Balance
If diuretic use has been excluded, measure arterial blood gases (ABG) and determine the acid-base balance.
Alkalosis
Alkalosis suggests one of the following:
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Vomiting
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Bartter syndrome
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Gitelman syndrome
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Diuretic abuse
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Mineralocorticoid excess
Acidosis
Acidosis suggests renal tubular acidosis type I or type II (eg, Fanconi syndrome). Other evidence of Fanconi syndrome, such as hypophosphatemia with phosphate wasting, hypouricemia, and renal glycosuria, may alert the clinician to this diagnosis. Renal tubular acidosis may also result from paraproteinemias, amphotericin use, gentamicin use, or glue sniffing (toluene toxicity [55] ). Patients with toluene toxicity may have a high anion gap with reduced kidney function.
Electrocardiogram
Perform an ECG to determine whether the hypokalemia is affecting cardiac function or to detect digoxin toxicity. The ECG may show atrial or ventricular tachyarrhythmias, decreased amplitude of the P wave, or appearance of a U wave.
ECG monitoring is imperative for severe hypokalemia (< 2 mEq/L in otherwise healthy individuals or < 3 mEq/L in patients with known or suspected cardiac disease). With a sudden shift of potassium into the cells (eg, with insulin therapy for diabetic ketoacidosis), even individuals with healthy hearts can develop lethal arrhythmias. Continuously monitor patients on digoxin or those with digoxin toxicity.
Although ECG changes may be helpful if present, their absence should not be taken as reassurance of normal cardiac conduction. [56] The ECG in hypokalemia may appear normal or may have only subtle findings immediately before clinically significant dysrhythmias. ECG findings may include the following:
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Ventricular dysrhythmia
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Prolongation of QT interval [57]
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ST-segment depression
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T-wave flattening
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Appearance of U waves
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Ventricular arrhythmias (eg, premature ventricular contractions [PVCs], torsade de pointes, ventricular fibrillation) [58]
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Atrial arrhythmias (eg, premature atrial contractions [PACs], atrial fibrillation)
During therapy, monitor for changes associated with overcorrection and hyperkalemia, including a prolonged QRS, peaked T waves, bradyarrhythmia, sinus node dysfunction, and asystole.
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A model of transport mechanisms in the distal convoluted tubule. Sodium-chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leaves the cell through the basolateral Cl− channel (ClC-Kb), and the Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the apical membrane, and a putative Na/Mg exchanger in the basolateral membrane. These transport mechanisms play a role in familial hypokalemia-hypomagnesemia or Gitelman syndrome.
