Potassium

 
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Physiology

Potassium is the major intracellular cation (intracellular K+ concentration is approximately 140 mEq/L) and is important for maintaining resting membrane potential of cells, particularly muscle and nerves. 60-75% of total body potassium is found within muscle cells, with the remainder in bone. Only 5% of potassium is located in extracellular fluid (ECF), therefore potassium concentration in blood is not always a reflection of total body potassium levels. Plasma (ECF) K+ concentration is tightly regulated; fairly small changes can have marked effects on organ function, with severe abnormalities of plasma K+ being life-threatening situations.

Plasma [K+] regulation

Regulation of plasma K+ is mostly accomplished by renal excretion and movement of K+ from extracellular fluid to intracellular fluid (translocation). If these mechanisms are functioning normally, the amount of K+ ingested has little effect on plasma K+. Intake has less of an effect on plasma potassium levels, however, if one or more of the regulatory mechanisms is faulty, then the amount of K+ ingested can exacerbate abnormalities in plasma K+.  In some species with high potassium diets (e.g. ruminants), changes in intake can affect plasma concentrations alone.

  • Intake: Ingested K+ is absorbed non-selectively in the stomach and small intestine. If dietary K+ is deficient, renal excretion of K+decreases (but still occurs) but excretion can increase under states of chronic high K+ in the diet.
  • Excretion: Potassium is excreted into the renal tubules and colon, with the latter contributing only a small amount to total Kexcretion. An additional source of potassium excretion is the saliva of ruminants.  Urinary excretion of K+ occurs in the distal tubules. About 70% of filtered K+ is absorbed in the proximal convoluted tubules of the kidney regardless of K+ balance (via solvent drag with water and passive paracellular diffusion), with 20% is absorbed in the ascending limb of the loop of Henle (via paracellular and transcellular absorption, the latter occurring via the NaK2Cl transporter). The remaining 10% is delivered to the distal nephron. Here,Kcan be excreted or resorbed depending on dietary intake (deficient = absorption dominates, chronic excess = mild excretion occurs).  Excretion occurs via principle cells in the connecting tubule, cortical collecting duct and first part of medullary collecting duct), with absorption of Na+ and is mediated by basolateral Na/K pumps and luminal transporters (there are three types, including the one responsible for potassium excretion in the loop of Henle and a different one that transports KCl) along with high conductance of the apical or luminal membrane of the cell. The activity of the Na/K pump is increased by aldosterone, resulting in net sodium absorption and potassium excretion. Absorption occurs transcellularly via α-intercalated cells (using a H-K-ATPase pump at the apical membrane) in the rest of the medullary collecting duct (other than the initial part) in exchange for H(activity of these cells results in excess hydrogen secretion or contributes to a metabolic alkalosis in states of hypokalemia).
    Excretion of K+ by the distal nephron is governed by the following, although the principle regulators are sodium absorption in the distal tubules and aldosterone:

    • Aldosterone: This increases activity of the basolateral Na/K pump, promoting K+ excretion in exchange for sodium and directly causes loss of potassium via increasing conductance of the luminal membrane. Aldosterone also promotes excretion of K+ in the colon. Aldosterone is stimulated by high potassium and hypovolemia.
    • Distal tubule flow rate: Increases in flow rate (osmotic diuresis, increased urine flow after fluid therapy, diuretics) enhances K+ secretion into the tubule lumen (excretion). This works via flushing K out (increasing lumen electronegativity) and enhancing distal sodium delivery.
    • Extracellular concentration of K+: Stimulates aldosterone release if high.
    • Renal tubular lumen electronegativity: Increased electronegativity enhances secretion into the tubule lumen.
    • pH: Acidosis decreases potassium excretion (see mechanisms below).
    • Diet: Dietary deficiency of Kwill stimulate resorption (although some Kis always lost in the urine) whereas chronic excess will stimulate excretion (via stimulating aldosterone release and the basolateral Na/K pump).
    • Concentration of NaCl in the distal tubule lumen: Low Na+ decreases secretion (high sodium would do the converse) whereas low Cl enhances secretion into the tubule lumen. This usually has minimal effect on potassium excretion or retention.
    • ADH: Stimulates secretion into the tubule lumen by opening up sodium/potassium changes in luminal membrane in principle cells of the collecting cortical duct) but also decreases excretion (by causing water absorption which decreases distal flow rates, reducing potassium excretion).
  • Translocation: Translocation of K+ into cells from the ECF is largely dependent on insulin and catecholamines, which stimulates uptake by cells. Tissue necrosis can also cause release of intracellular potassium, particularly in skeletal muscle. Shifts of K+ in and out of cells can also occur with changes in the pH of ECF. Specifically, alkalosis causes potassium to move into cells resulting in hypokalemia, whereas a mineral metabolic acidosis (hyperchloremic) can directly cause a transient hyperkalemia by stimulating potassium movement out of cells (or decreased potassium uptake by cells). In contrast an organic acidosis (titration or high anion gap acidosis) does not directly cause a hyperkalemia through translocation. The hyperkalemia that is frequently seen in animals with a titration acidosis, is thought to be secondary to decreased renal excretion not translocation (see mechanisms below) (effect of pH on renal handling of potassium is reviewed by Hamm et al 2013).

Methods

Serum or plasma concentrations of these major electrolytes can be measured by ion-specific electrodes or flame photometry. Measurement of electrolytes by ion-specific electrodes is called potentiometry. There are two types of potentiometry: direct and indirect. Direct potentiometry is utilized by blood gas machines and does not involve sample dilution. Indirect potentiometry is utilized by automated chemistry analyzers, such as the ones used at Cornell University, and involves sample dilution before analysis. This distinction is important because endogenous interferents such as lipemia may falsely decrease electrolyte concentrations with indirect, but not direct, potentiometry.

Technique used at Cornell

Direct (blood gas machine) or indirect (chemistry analyzer) potentiometry. On our chemistry profiles, indirect potentiometry is used to obtain potassium results.

Procedure

With this technique, an electrode containing an internal electrolyte solution is immersed in the patient sample, which is separated from the internal solution by a membrane that can detect the electromotive force (EMF) generated by the ions in both solution. This EMF is determined by the difference in concentration of the test ion in the test solution and internal filling solution (test ion at fixed concentration). The EMF is predicted by the Nernst equation (see techniques for more details on the method). For testing purposes with the chemistry analyzer, the sample is diluted 1:32 before analysis (indirect potentiometry).

Units of measurement

The concentration of potassium is measured in mEq/L (conventional units, used at Cornell), mg/dL (conventional units), or mmol/L (SI units). The conversion formula is shown below:

mEq/L x 1 = mmol/L
mg/dL ÷ 3.9 = mmol/L

Sample considerations

Sample type

Serum, plasma, and urine. Plasma provides more accurate values than serum because potassium is released from platelets during clotting.

Anticoagulant

Heparin is the preferred anticoagulant. K3EDTA should be avoided because it will cause spuriously high levels of K+ in sample due to potassium in the anticoagulant.

  • Bovine: Internal studies in the Clinical Pathology Laboratory at Cornell University in bovine blood show that values in heparinized plasma are slightly higher (0-0.3 mEq/L)  than in serum (Naeves and Stokol, unpublished data).

Stability

  • Human: Per reagent manufacturer product information sheet
    • Serum and plasma: 2 weeks at room temperature, 2 weeks refrigerated.
    • Urine: Store at 4°C
  • Bovine: Internal studies in the Clinical Pathology Laboratory at Cornell University show that potassium is more stable in heparinized whole blood versus unseparated clotted whole blood and is more stable at 22°C than 4°C. The increased stability at 4°C is attributed to increased inhibition of the Na/K ATPase in cells (which drives K in and sodium), resulting in higher extracellular potassium.
    • Heparin/green top tubes: Potassium results are more stable in heparinized whole blood samples (not separated) maintained at 22°C (no change in results at 4 or 6 hours after collection) compared to 4°C (increased by 0.1-0.2 mEq/L by 4 hours and by 0.2-0.3 mEq/L at 6 hours) after collection.
    • Clot tubes: Potassium values are mildly increased in whole blood maintained at 4°C (by 0.1-0.3 mEq/L) or 22°C (by 0.1-0.2 mEq/L)  for 4 hours (Naeves and Stokol, unpublished data).

Regardless of the above findings in cattle, which only pertain to storage for up to 4-6 hours, it is still recommended that serum or plasma should be removed immediately from cells after collection (by centrifugation), to avoid falsely increased Klevels, caused by release of K+ from intracellular stores in cells (potassium is much higher in cells than in ECF). Red blood cells and platelets are the major sources of intracellular potassium, however only certain species (horses, some breeds of cattle such as Holstein, pigs, llamas) have high potassium in red blood cells. Dogs do not have high potassium in red blood cells, except for certain breeds of dogs (Japanese or other Asian breeds, e.g. Akita, Shiba Inu). Also, reticulocytes in all dog breeds are rich in potassium. Leakage of potassium from cells can occur without overt hemolysis and will also occur in serum separator tubes if serum is not separated from the red blood cells. A falsely high potassium is one of the most common artifacts seen on chemistry panels from samples that are mailed Cornell laboratory from horses, camelids and cattle (since we see blood from Holsteins, primarily), when the serum or plasma has not been separated from cells.

Interferences

  • Lipemia: Marked lipemia may falsely decrease potassium due to solvent exclusion effect.
  • Hemolysis: Hemolysis may increase serum or plasma potassium in species or breeds with high potassium red blood cells (horses, camelids, pigs, some breeds of cattle such as Holstein, some Asian dog breeds) or in dogs with a marked reticulocytosis.
  • Icterus: No effect.

Test interpretation

Hyperkalemia

Hyperkalemia increases the resting membrane potential (i.e. makes it less negative so that it is easier to polarize or become activated, e.g. increase from -90 to -80). This predisposes the cell to being over-excitable and results in muscle and nerve excitability, the most serious consequence of which is cardiac arrythmias and even arrest (remember, high KCl can be used as a euthanasia solution to induce cardiac arrest). Hyperkalemia can potentially contribute somewhat to an acidosis by inhibiting renal ammoniagenesis (the main way the kidney eliminates acids) (Hamm et al 2013).

  • Artifact:
    • Serum: Serum K+ is generally higher than plasma K+ due to release of K+ from platelets during clotting. Based on internal studies at Cornell (such as when we established our reference intervals on serum and plasma from related species) and previous reports, the difference between serum and plasma K+ in animals with normal platelet counts can be as high as 0.7 mEq/L in dogs, 1.6 mEq/L in cats, 1.6 mEq/L in horses, 0.5 mEq/L in Holstein cattle (this may be due to hemolysis in the samples) and 0.8 mEq/L in alpacas. This difference could be higher (but not hugely) in animals with thrombocytosis (unless marked, i.e. > 1 million/uL). Thus, heparinized plasma is the preferred sample for potassium measurement.
    • Hemolysis (in vivo or in vitro) or leakage from RBCs: Intravascular (in vivo) hemolysis in a hemolytic anemia, artifactual (in vitro) hemolysis or leakage from RBCs with storage or poor sample handling, may increase K+ in animals with high K+ in their erythrocytes, including horses, pigs (Di Martino et al 2015), some cattle breeds (e.g. Holstein) and camelids. This will depend on the degree of hemolysis or RBC membrane disruption (more likely if high). A high potassium is one of the most common falsely abnormal chemistry results (along with falsely low glucose) in mailed in samples, in which serum or plasma has not been separated from cells in these aforementioned species. Certain dog breeds also have high K+ in their mature red blood cells, such as Akitas and other Japanese breeds. All dogs have high K+ in their reticulocytes, so K+ can be falsely increased  in hemolyzed samples (or samples with delayed separation from cells) with very high reticulocyte counts from any dog breed.
    • Leukocytosis: Very high leukocyte counts (> 100,000/uL) can potentially result in hyperkalemia due to leakage of intracellular K+ from cells. We have not really identified such cases.
    • K+ EDTA anticoagulant: Contamination of serum/plasma sample with K+ EDTA will result in very high (non-physiologic) K+ values (>20 mEq/L) as well as marked hypocalcemia (<5 mg/dL; due to chelation). We see this unavoidable artifact occasionally in samples.
    • Contamination with high potassium fluids: If a blood sample is taken from an unflushed intravenous line used to administer potassium-rich fluids, K+ could be falsely high.
  • Physiologic:
    • Age: Potassium is reported to be higher in foals < 5 months of age than adult horses. Foals < 1 week old are reported to have higher K+ than foals > 1 week old.
  • Iatrogenic: Supplementation of potassium in intravenous fluids does not usually result in hyperkalemia if kidney function is normal.
  • Pathophysiologic:
    • Transcellular shifts: Shifting of K+ from intracellular fluid (ICF) to ECF occurs with substantial tissue necrosis, exercise (this occurs especially in horses and is due to release of K+ from muscles, particularly skeletal muscles which are of high mass; K+ is a local vasodilator for muscle cells), uroperitoneum (in foals and small animals – shifts from abdomen where urine is high in K+ into blood), hypertonicity (e.g. diabetes mellitus; occurs due to solvent drag), insulin deficiency (e.g. diabetes mellitus) and potentially a hyperchloremic metabolic acidosis (a transient hyperkalemia is seen after experimental infusion of ammonium chloride in dogs). A high anion gap or titration metabolic acidosis (accumulation of a non-chloride acid, e.g. lactate, phosphate) does not usually result in hyperkalemia. Hyperkalemia in animals with a titration acidosis is usually not due to translocation, but is thought to be due to decreased renal excretion of K+ (see below).
      • Hyperkalemic polymyopathy of horses: This is due to a genetic defect in the alpha subunit of the sodium channel of muscle cells (the sodium channels remain perpetually open) observed in Quarterhorses and other heavily muscled breeds like Appaloosas and Paints. It is a familial condition in the Quarterhorse and appears to be inherited as an autosomal dominant condition. The condition appears to be clinically worse in males. It is characterized by intermittent episodes of muscle fasciculation and weakness concurrent with increases in serum K+ values, which is likely due to leakage from muscle due to the defective channels. Normokalemic variants have been described.
    • Decreased renal excretion: Hyperkalemia is a feature of anuric or oliguric acute renal failure, urinary tract obstruction or rupture (as indicated above), and hypoaldosteronism (Addison’s disease).
      • Addison’s disease (hypoaldesteronism) causes a low sodium and high potassium with a sodium:potassium ratio of < 27:1. Electrolyte changes (high K+, low Na+) mimicking Addison’s disease can be seen with repeated drainage of thoracic effusions, severe diarrhea (e.g. Salmonella or whipworm infection), and lymphangiosarcoma, although the precise mechanism is unclear. Measurement of the sodium to potassium ratio is not a sensitive or specific diagnostic test for Addison’s disease (it will be normal in variants of Addison’s disease, in which mineralocorticoids are normal but glucocorticoids are deficient). This is most common in the dog and rare in other species. It is reported that horses in chronic renal failure can have high potassium, which is attributed to secondary hypoaldosteronism.
      • Acidosis: Acidosis (metabolic or respiratory) decreases K+ excretion and promotes resorption in the distal nephron. Decreased excretion is due to decreased activity of the basolateral Na/K pump (that drives potassium excretion in principle cells in the distal nephron) and higher resistance (decreased conductance) of the apical membrane of principle cells. Decreased excretion is also thought to be secondary to increased renal ammoniagenesis – ammonia inhibits sodium absorption in the collecting duct and may affect the luminal K channels (both of which normally drives potassium excretion). Potassium absorption by intercalated cells is stimulated via acidosis activating the H/K pump (causing distal tubular excretion of hydrogen, an appropriate corrective response to a metabolic acidosis and a compensatory response to a respiratory acidosis) in exchange for absorption of potassium. However, remember that potassium excretion will often be increased in disease states associated with a metabolic acidosis, in particular. For instance, with hypovolemia stimulating lactic acidosis, even though the acidosis may be promoting potassium absorption/decreased excretion (which will increase potassium in blood), aldosterone and ADH will be stimulating sodium and water resorption, which will cause potassium excretion. The aldosterone response will have a far greater effect on potassium than the acidosis due to the over-riding need to retain sodium (and water) to minimize the hypovolemia. In addition chronic acidosis actually inhibits proximal tubular sodium (and water) absorption leading to increased distal flow rates and potassium excretion (Hamm et al 2013).
    • Other mechanisms
      • Decreased salivary excretion: Marked dehydration in ruminants could cause a hyperkalemia due to decreased saliva production, particularly if there is concurrent renal dysfunction. This is quite uncommon, since anorexic cattle often have low potassium, which offsets any increases from decreased saliva production.

Hypokalemia

Hypokalemia decreases the resting membrane potential of cells (i.e. makes it more negative, which hyperpolarizes the cells, making them less sensitive to stimuli, e.g. -90 to -95). This means that muscles and nerves are weaker and require larger stimuli to be activated resulting in muscle weakness and arrythmias. Hypokalemia also interferes with ADH action on renal tubules and alters blood flow through the vasa recta, depleting the medullary interstitium of solutes, contributing to defective concentrating ability. Hypokalemia also contributes to (or worsens) or causes a metabolic alkalosis (in states of chronic hypokalemia, which is rare in veterinary medicine) by stimulating hydrogen excretion in the proximal and distal tubules. In the proximal tubule, the luminal Na/H pump and basolateral Na/bicarbonate transporter are stimulated, resulting in net resorption of sodium and bicarbonate, in exchange for hydrogen loss. In the distal tubule, both the luminal H/K pump and H-ATPase pump are stimulated resulting in hydrogen excretion in exchange for potassium absorption. In a pre-existing metabolic alkalosis (e.g. displaced abomasa in ruminants), depletion of potassium can exacerbate the alkalosis via stimulating renal hydrogen excretion in proximal and distal tubules (which is worsened by sodium avidity in the kidney, which promotes sodium resorption with bicarbonate) (Hamm et al 2013). Hypokalemia is usually due to gastrointestinal or renal losses of potassium. Remember that blood K+ values are not always a reflection of total body K+ stores; K+ values can be normal in blood, despite severe deficits in total body K+.

  • Artifact: Severe lipemia and possibly hyperglobulinemia (due to immunoglobulins) may result in a mild hypokalemia (pseudohypokalemia) due to solvent exclusion/volume displacement when potassium is measured using diluted plasma (indirect potentiometry; the technique routinely used for electrolyte measurement). This artifact can be overcome by using undiluted plasma (direct potentiometry) for measuring potassium (i.e. a blood-gas analyzer). The changes in potassium with solvent exclusion are far less than those seen with sodium and chloride.
  • Pathophysiologic:
    • Decreased intake: This occurs with anorexia (not just inappetance or decreased appetite) in large animals, including horses (especially foals), camelids and cows. Decreased intake in small animals rarely results in hypokalemia unless there are additional losses of potassium. Hypokalemia can be seen in cats fed low potassium diets.
    • Transcellular shifts: Shifting of K+ from ECF to ICF occurs with primary respiratory or primary metabolic alkalosis resulting in alkalemia (where hydrogen moves extracellularly in exchange for potassium), insulin release (usually spikes of insulin such as that seen after glucose infusion or eating) or administration, and catecholamine release (from epinephrine stimulating β2-adrenergic receptors and activating the sodium-potassium [Na/K] ATPase pump in muscle). Similarly, endotoxemia may also result in hypokalemia because endotoxins also stimulate the Na/K ATPase pump in muscle cells and promote insulin release. Transcellular shifting due to alkalemia usually produces small changes in potassium (unless there are concurrent losses of potassium).
    • Increased loss: The potassium deficit will be enhanced if intake of potassium is decreased.
      • Gastrointestinal losses: Causes include vomiting of gastric contents (the loss of chloride enhances K+ excretion in the kidneys, promoting the hypokalemia), abomasal stasis (e.g. vagal digestion or atony), outflow obstruction or torsion, and diarrhea. Diarrhea in horses and cattle often produces a hypokalemia. Severe diarrhea and vomiting in dogs and cats can also result in hypokalemia. Saliva is potassium-rich and disorders such as choke in horses and cattle can result in hypokalemia.
      • Third space losses/sequestration: Accumulation of fluid in body cavities (e.g. peritonitis) or distended gastrointestinal system (e.g. volvulus, ileus) can result in hypokalemia. This may be dilutional from perceived volume depletion due to losses of fluid from the intravascular space, which results in secretion of ADH (retains water in kidney) and stimulation of thirst.
      • Cutaneous losses: Sweating (horses).
      • Renal losses: Renal losses of potassium can occur via several mechanisms, the main one being aldosterone, which stimulates sodium absorption in exchange for potassium excretion in the principle cells of the collecting ducts.
        • Aldosterone is stimulated by the renin-angiotensin system in response to hypovolemia and decreased delivery of chloride (hypochloremia) to the macula densa. Hyperaldosteronism is a rare condition causing severe hypokalemia in dogs and cats and is usually secondary to adrenal neoplasia (in dogs) or hyperplasia (cats).
        • Increased distal tubular flow rate: Potassium excretion is also enhanced by increased distal tubule flow rates, i.e. any cause of polyuria (e.g. glucosuria, post-obstructive diuresis)
        • Increased lumen electronegativity, e.g. high concentrations of unadsorbable anions in the renal tubule lumen, e.g. penicillin, ketones, decrease the positive charge within the lumen, which causes the positively charged potassium to get excreted.
        • Primary metabolic alkalosis: Hydrogen is released from internal cellular buffers (e.g. hemoglobin)  into blood to buffer the accumulated bicarbonate. To maintain electroneutrality, potassium moves into cells. In the renal tubules, this will create a concentration gradient between the cell and the renal tubular lumen that will promote potassium excretion into the lumen. In addition, alkalosis increases the activity of the potassium channels in principle cells (promoting excretion). Excretion will also be promoted by increased bicarbonate in the urine (increasing lumen electronegativity) and low urine chloride (frequently seen with metabolic alkalosis – the low chloride stimulates activity of the luminal KCl channel in the principle cell) (Hamm et al 2013)
        • Renal tubular disease: Potassium wasting also occurs if there is renal tubule disease that prevents the normal absorption of filtered potassium, e.g. proximal renal tubular acidosis, chronic renal disease in cats.
        • Loop diuretics: These inhibit the NaK2Cl pump in the thick ascending limb of the loop of Henle. The lack of K+ absorption is exacerbated by a luminal K channel, which secretes K+ actively into the urine (which is normally required for correct operation of the NaK2Cl pump).
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