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Potassium is the most abundant cation in the intracellular fluid and it plays a vital role in the maintenance of normal cell functions. Thus, potassium homeostasis across the cell membrane, is very critical because a tilt in this balance can result in different diseases that could be life threatening. Both Oxidative stress (OS) and potassium imbalance can cause life threatening health conditions. OS and abnormalities in potassium channel have been reported in neurodegenerative diseases. This review highlights the major factors involved in potassium homeostasis (dietary, hormonal, genetic, and physiologic influences), and discusses the major diseases and abnormalities associated with potassium imbalance including hypokalemia, hyperkalemia, hypertension, chronic kidney disease, and Gordon’s syndrome, Bartter syndrome, and Gitelman syndrome.
Electrolyte balance is important for general functioning of the body, and it is closely monitored in clinical settings because electrolytic abnormalities are caused by a wide variety of factors and may lead to a wide variety of disorders. The most common electrolytes in the body are sodium, potassium, and chloride. Often measured in the lab using ion selective electrodes (ISE) technology. Maintenance of the balance between water and electrolyte composition of the body in a healthy individual requires specific stringent homeostatic mechanisms. Water constitutes 60% of the lean body mass and it is described in terms of intracellular fluid (ICF) and extracellular fluid (ECF). ECF includes the fluid inside blood cells and blood plasma. A constant osmotic equilibrium is maintained between the ICF and ECF, however their electrolyte composition differs. ECF contains mostly sodium cations while the ICF has an abundance of potassium cations primarily in muscles 1–4.
However, about 2% of the total body potassium can be found in the ECF. In a normal healthy person, the plasma potassium is maintained within a narrow range of 3.5–5.0 mEq/L 5.
Potassium homeostasis involves redistribution of potassium between cells ICF and the ECF. The control of the movement of potassium from intracellular to extracellular space is one of the ways that the body’s potassium balance is maintained. The body has a way to maintain this balance for example, when potassium is lost through the renal system, the body pushes out cellular potassium which prevents the expected drop in plasma potassium level. Potassium intake, renal excretion, loss through the gastrointestinal tract are crucial in potassium homeostasis 6.
Potassium homeostasis is highly influenced by the activities of the sodium and potassium pump (Na+-K+-ATPase) which facilitates the active transport of sodium and potassium ions across the cell membrane against their concentration gradients. The Na+-K+-ATPase is found in the membrane of almost all animal cells and it pumps sodium ions (Na+) out of the cell and potassium ion (K+) into the cell. This pump keeps the K+- balance between the ICF and ECF primarily through a buffering that involves hydrolysis of ATP to generate energy, and for each ATP hydrolyzed, two K+ are transported inside while three Na+ are pushed out of the cell. This maintains high Na+ in the ECF and high K+ in the ICF and creates an electrical gradient 7. The cytoplasm becomes negatively charged as the number of Na+ leaving the cell is higher than the number of K+ entering the cell (i.e. more positive charged ions leave the cell). This electrical gradient is used in neurons and muscles for nervous system function and muscular contraction 8. This K+ and Na+ interchange influences K homeostasis. When the body needs to retain more Na+, renal K+ secretion is induced leading to an increase in the delivery and reabsorption of Na+ by the distal nephron. This conversely forces the passive K+ efflux across the apical membrane 9.
Apart from K+ loss through the renal system, extrarenal mechanisms also affect the normal potassium homeostasis. Extrarenal mechanism include potassium uptake by both liver and muscle generally, and intestinal secretion of potassium. Extrarenal tissues regulate acute potassium tolerance while the kidneys manage chronic potassium balance. Several hormones, including insulin, epinephrine, aldosterone, and glucocorticoids are involved in the maintenance of normal extrarenal potassium metabolism10. These hormones enhance potassium uptake by the liver and muscle. The in and out of cell movement of potassium could be also affected by changes in acid-base balance 11. This depends on the exchange of hydrogen ions for potassium across the cell membrane. A shift of H+ out of the cell and potassium into the cell occurs when there is an increase in serum pH (decrease in H+ concentration). Conversely, under acidic condition (acidemia) a shift of potassium out of the cell occurs. A significant rise in serum potassium may result from a sudden increase in plasma osmolality which shifts water out of the cell and drags in some potassium with the water 12.
A screenshot of the major conditions associated with potassium imbalance which causes different health abnormalities and diseases is shown in Figure 1 and these conditions include hypo and hyperkalemia, pseudohyperkalemia, and pseudo-hypoaldosteronism 13–17. They are disccussed more in detail later in this review.
The kidney is the seat of the body’s K+ metabolism and it maintains the body’s K+ content by controlling K+ intake and K+ excretion/loss. Figure 2 (adapted from Rastegar, 1990 12), shows the factors that affect renal potassium excretion. Some of the important factors regulating K+ movement across the cell under normal conditions are insulin and catecholamines 18. Insulin, catecholamines, aldosterone, and alkalemia force potassium into the cells while increase in osmolality, and acidemia shift potassium out of the cell 12. The kidney moderates the activities of aldosterone which when over produced facilitates K+ loss. Under normal conditions, intracellular K+ buffers the effect of a fall in extracellular K+ concentrations by moving into the extracellular space but the over production of aldosterone affects this balance and causes continued loss of K+ 19. Another organ involved in K+ homeostasis is the colon. The colon is the major site of gut regulation of potassium excretion. Potassium excretion via the colon is minimal during normal conditions but its role increases as the renal function worsens as seen in renal insufficiency or during acute potassium overload when the kidneys are overwhelmed 12,20.
Skeletal muscle is also implicated in extracellular K+ concentration regulation. This was demonstrated by studies in rats using a K+ clamp technique. According to the report, there was a decrease in muscle sodium pump pool size due to K+ deprivation. Also, glucocorticoid treatment induced increase in muscle Na+-K+-ATPase alpha2 levels. Furthermore, the body can adapt to changes in renal and extrarenal K+ balance without significantly altering plasma K+ level 21. The Na+-K+-ATPase mechanism is still under investigation. However, there is evidence that insulin may influence the activity and expression of muscle Na+-K+-ATPase. Insulin forces K+ into the cells. Insulin apart from regulating glucose metabolism after a meal also shift dietary K+ into cells until the kidney excretes the K+ load to re-establish K+ homeostasis22–24. The ability of skeletal muscle to buffer declines in extracellular K+ concentrations by donating some component of its intracellular stores25.
There are also genes involved in K+ homeostasis especially WNK genes which act at the distal convoluted tubule (DCT). The WNK genes act as molecular switch and activates the thiazide-sensitive NaCl cotransporter (NCC). Low intracellular chloride level triggers the activation of NCC by WNK kinases resulting in reabsorption of potassium at the DCT and preventing loss of potassium 26. Mutation of the WNK1 and WNK4 genes were observed in some patients with hyperkalemia and hypertension caused by pseudohypoaldosteronism type II 27.
Oxidative stress (OS) is known to adversely affect health outcomes in humans. It influences the activities of inflammatory mediators and other cellular processes involved in the initiation, promotion and progression of human neoplasms and pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, Lou Gehrig’s disease, multiple sclerosis and Parkinson’s disease, as well as atherosclerosis, autism, cancer, heart failure, and myocardial infarction 28,29. Likewise abnormalities in potassium channel have been reported in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease commonly called Lou Gehrig’s disease30, and Parkinson’s disease such that potassium channel blockers are part of treatment regimen in Parkinson’s disease 31. Enzymes that are involved in OS also affect potassium activities. An example is heme oxygenase-1 (HO-1) whose expression is increased in the central nervous system (CNS) following an ischemic insult. HO-1 is active in cancer cells and is suggested to also increases expression of HO-1 can induced apoptosis by regulating K(+) channels especially regulation of Kv2.1 32. Koong and co with the knowledge that active oxygen species are produced postischemic reperfusion studied how free radicals produced after exposure to hypoxia and reoxygenation activate voltage-dependent K+ ion channels in tumor cells in vitro. They reported that potassium (K+) channels are activated following reoxygenation suggesting that the activation of K+ currents is one of the early responses to oxidative stress 33.
Potassium-rich foods include meats (pork), fish (rockfish, cod and tuna), milk, yogurt, beans (soybeans, lima beans, and kidney beans), tomatoes, potatoes, spinach, carrot, and fruits (bananas, beet green, prune juice, peaches, oranges, cantaloupe, honeydew melon and winter squash) 34. Ingestion of K+ rich diets influences plasma concentration of potassium 6. Increased potassium intake can occur through intravenous (IV) or oral potassium supplementation. Another potential but very rare source is hemolysis from packed red blood cells (PRBCs) transfusion 35. Enteric solute sensors are said to modulate the activities of dietary Na+, K+, and phosphate. After meal, the enteric sensors detect these ions and send signals to the kidney to buffer the effect through ion excretion or reabsorption. Through this mechanism the enteric sensors may enhance the clearance of the K+ from diet or infusion 36–38. A study has also suggested that dietary K+ intake through a splanchnic sensing mechanism can signal increases in renal K+ excretion independent of changes in plasma K+ concentration or aldosterone 20.
Aldosterone, a mineralocorticoid hormone is known to moderate the body’s electrolyte balance including potassium10. It is involved in the response to two opposite physiological conditions (aldosterone paradox): hypovolemia and hyperkalemia. One of its key mechanisms is the stimulation of Na+ reabsorption and K+ secretion in the aldosterone-sensitive distal nephron (ASDN) 39. Aldosterone acts by increasing the number of open sodium channels in the luminal membrane of the principal cells in the cortical collecting tubule, leading to increased sodium reabsorption hyperkalemia 40. Aldosterone and renin-angiotensin system work together under hypovolemic condition. Low volume triggers activation of the renin-angiotensin system which induces increased aldosterone secretion 41. The increase in circulating aldosterone stimulates renal Na+ retention that facilitates the restoration of extracellular fluid volume without affecting renal K+ secretion. However, during hyperkalemia, aldosterone release is mediated by a direct effect of K+ on cells in the zona glomerulosa. The increase in circulating aldosterone stimulates renal K+ secretion which restores the serum K+ concentration to normal without affecting renal Na+ retention 6,10.
Understanding aldosterone paradox is a complex process and it is important for the kidney to differentiate between the two opposite conditions for effective response. Angiotensin II is suggested as the key sensor of the difference between volume depletion and hyperkalemia. This is because activation of the renin-angiotensin-aldosterone system (RAAS) controls volume depletion and angiotensin II is not affected by plasma K+ concentration 18. Also, renal K+ secretion and Na+ retention remain stable under normal condition but under pathophysiologic conditions there is increase in distal Na+ and water delivery coupled to increased aldosterone levels which results in renal K+ wasting 18. A recent study suggests that a blockade of renin-angiotensin-aldosterone activity may adversely affect extrarenal/transcellular potassium disposition as well as cause a reduction in potassium excretion in humans with renal impairment. Reduced aldosterone production impairs the responsiveness of the renal system and potassium metabolism 42,43. Aldosterone is a drug target for certain human diseases. For example, reducing plasma aldosterone level has shown promises in reducing the risks associated with cardiovascular and renal problems in hypertensive humans but can produce hyperkalemia 42. An emerging study is suggesting that microRNAs may be involved in the modulation of renin-angiotensin-aldosterone system that triggers cardiovascular inflammation seen in potassium imbalance 44.
Vasopressin is an important hormone that affects renal K+ balance. Vasopressin stabilizes renal K+ secretion during changes in flow rate 45. Arginine vasopressin (AVP) can induce an increase of low-conductance K+ channel activity of principal cells in rat cortical collecting duct (CCD) by the stimulating cAMP-dependent protein kinase. An increase of low-conductance K+ channel activity may lead to hormone-induced K+ secretion in a rat CCD. And a combination of endogenous vasopressin suppression and decreased distal K+ secretion can prevent excessive K+ loss under full hydration and water diuresis 46.
The activities of some genes have been identified to regulate potassium homeostasis. Notable among the genes are mammalian with-no-lysine K (WNK) kinases which are a family of four serine-threonine protein kinases, WNK1–4. Mutations of WNK1 and WNK4 in human cause pseudohypoaldosteronism type II (PHA2), an autosomal-dominant Mendelian disease characterized by hypertension and hyperkalemia 47. WNK proteins act as molecular switches with discrete functional states that have different effects on downstream ion channels, transporters, and the paracellular pathway. Mutations in the gene encoding the kinase WNK4 can cause pseudohypoaldosteronism type II (PHAII). PHAII also called Gordon syndrome is a rare syndrome featuring hypertension and hyperkalemic metabolic acidosis. Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC 48. Further explanation of aldosterone paradox has been made by the implication of the activity of the WNK4 in the distal nephron. These effects enable the distal nephron to allow either maximal NaCl reabsorption or maximal K+ secretion in response to hypovolemia or hyperkalemia, respectively 49. WNK4 has shown interaction with claudin group of proteins (claudin 1 (CLDN1), claudin 2 (CLDN2), claudin 3 (CLDN3), and claudin 4 (CLDN4)]. This interaction network illustrated in Figure 3 was created using MiMI plugin for cytoscape 50.
Claudins are tight junction proteins involved in forming a physical barrier around cell to prevent solutes and water from passing freely through the paracellular space 50,51. CLDN2 forms a cation-selective pore in tight junctions while CLDN4 restricts the passage of cations through epithelial tight junctions. Claudins 1, 3, and 4 may be involved in separating the potassium-rich endolymph from the sodium-rich intrastrial fluid52. Other genes that network with WNK4 are SLC12A3 solute carrier family 12 (sodium/chloride transporter), member 3. SLC12A3 contributes in maintaining electrolyte homeostasis by encoding a renal thiazide-sensitive sodium-chloride cotransporter which mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome. Chloride Channel, Voltage-Sensitive Kb (CLCNKB) gene is another gene that is involved in potassium homoestasis. The CLCNKB is expressed predominantly in the kidney and may be important for renal salt reabsorption. A mutation in CLCNKB results in hypokalemia as seen in autosomal recessive Bartter syndrome type 3 (BS3) 53–55. Aldosterone also stimulates the expression of the serum- and glucocorticoid-inducible kinase 1, which enhances the abundance of the epithelial sodium channel, activates basolateral Na+/K+-ATPase activity 39,56. This increases the electrochemical driving force for sodium reabsorption and K+ excretion57 necessary for potassium homeostasis regulation.
The urinary system is the major site of potassium homeostasis regulation and under normal physiological conditions, about 90% of potassium is excreted through the urine while the remaining 10% or less is excreted through sweat, vomit, or stool 58,59. There are differences at the rate at which potassium is secreted or excreted as the urine travels along the renal tubule. Most potassium excretion occurs in the principal cells of the cortical collecting duct (CCD) 58. The late distal convoluted tubule (DCT), the connecting tubule (CNT), and the cortical collecting duct (CCD) are the segments primarily involved in renal K+ secretion and they are collectively called the aldosterone-sensitive distal nephron (ASDN). This is because basal K+ secretion in these segments involves the renal outer medullary K+ channel (ROMK) whose activity and abundance is influenced by aldosterone. Potassium/sodium pump determines where, when and the amount of potassium to be excreted. That is why luminal sodium delivery to the distal convoluted tubule (DCT) and the cortical collecting duct (CCD) control urinary potassium excretion. Aldosterone and other adrenal corticosteroids with mineralocorticoid activity affect the rate of potassium secretion 60. The rates of Na+ reabsorption as well as K+ secretion can be related to tubular flow rates. Sodium reabsorption through epithelial sodium channels (ENaC) located on the apical membrane of cortical collecting tubule cells is driven by aldosterone and generates a negative electrical potential in the tubular lumen, driving the secretion of potassium at this site through the renal outer medullary potassium (ROMK) channels61. An increase in tubular flow rates can directly affect the activity of apical membrane Na+ channels and indirectly activate a class of K+ channels, referred to as maxi-K, which under low flow states are functionally inactive. This suggests that an increase in glomerular filtration rate (GFR) after a protein-rich meal would lead to an increase in distal flow activating the ENaC, increasing intracellular Ca2+ concentration, and activating maxi-K+ channels. The body uses this process to guide against development of hyperkalemia as more K+ are secreted and eliminated 62. Renal potassium excretion can also be affected by some medications such as potassium-sparing diuretics, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs NSAIDs, and renin-angiotensin aldosterone system (RAAS) inhibitors 63–66.
Like most body’s physiologic processes, K+ secretion/excretion is regulated by circadian rhythm. The rate of urinary K+ excretion changes during a 24-hour period and this may be due to changes in activity and fluctuations in K+ intake caused by the spacing of meals. The circadian rhythm effect is used to explain why K+ excretion is lower at night and in the early morning hours and then increases in the afternoon in situations when K+ intake and activity are evenly spread over a 24-hour period. The kidney is the principal organ responsible for the regulation of the composition and volume of extracellular fluids (ECF). Several major parameters of kidney function, including renal plasma flow (RPF), glomerular filtration rate (GFR) and tubular reabsorption and secretion have been shown to exhibit strong circadian oscillations. Renal circadian mechanisms contribute in maintaining homeostasis of water and three major ions (Na+, K+ and Cl−) and dysregulation of the renal circadian rhythms may lead to the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans 67–70.
Potassium is very important for regulating the normal electrical activity of the heart. A shift in potassium balance will adversely affect the heart 71. Hypokalaemia may result in myocardial hyperexcitability which may lead to re-entrant arrhythmias. Conversely, increase in extracellular potassium reduces myocardial excitability Electrocardiogram (EKG or ECG) taken in hypokalaemic state show increased amplitude and width of the P wave, prolongation of the PR interval, T wave flattening and inversion, ST depression, prominent U waves, and an obvious long QT interval because of fusion of the T and U waves 72. Also, supraventricular and ventricular ectopics, supraventricular tachyarrhythmia and develop life-threatening ventricular arrhythmias and Torsades de Pointes develop as hypokalemic condition persists 73. Hypokalaemia is often associated with hypomagnesemia, which increases the risk of malignant ventricular arrhythmias 74. On the other hand, persistent hyperkalemia suppresses impulse generation leading to bradycardia and conduction blocks and eventually cardiac arrest 75. However, serum potassium level does not always correlate with the ECG changes. Thus, patients with relatively normal ECGs may still experience sudden hyperkalemic cardiac arrest 76. Also, hypo/hyperkalemia can cause cardiac arrest in children 77.
Abnormal low blood potassium level of < 3.5 mEq/L is referred to as hypokalemia and it is a common electrolyte disorder in clinical practice 14. Hypokalemia can result from inadequate potassium intake, excessive loss of potassium, and transcellular shift of potassium which is an abrupt movement of potassium from the extracellular fluid into intracellular fluid in the cells. Often hypokalemic condition is caused by drugs prescribed by physicians or due to inadequate intake. Abnormal losses can occur through renal system induced by metabolic alkalosis or loss in the stool induced by diarrhea. Metabolic alkalosis is always associated with hypokalemia and it is a salt sensitive disorder in which there is selective chloride depletion resulting from vomiting or nasogastric drainage. Chloride induced alkalosis can be corrected by administration of chloride and this allows the body to replenish its potassium store if potassium intake is insufficient. Over production of aldosterone (hyperaldosteronism) also causes metabolic alkalosis related severe hypokalemia (serum potassium, < 3.0 mEq/L). There is a relationship between Cushin’s syndrome and hypokalemia 14. Metabolic Acidosis especially type I or classic distal renal tubular acidosis associated with hypokalemia. Interestingly the severity of this condition is determined by the dietary sodium and potassium intake and serum aldosterone concentrations instead of the degree of acidosis. Untreated distal renal tubular acidosis could lead to a life-threatening hypokalemic level (serum potassium, < 2.0 mEq/L). As mentioned earlier hypokalemia can result from extrarenal potassium loss as seen in colonic pseudo-obstruction (Ogilvie’s syndrome) 78. The factors that decrease plasma potassium level are shown in Table 1.
In the diagnosis of hypokalemia, it is important to differentiate true potassium depletion from Pseudohypokalemia which may be transient and arise from sampling errors, for instance if a blood sample is taken upstream of an infusion of saline, dextrose, or other fluids that have little or no potassium. Sampling error may be confirmed from other hematological tests that will demonstrate that the collected sample is a mixture of blood and infused fluid. Some of the important tests for hypokalemia differential diagnosis include measurement of blood magnesium, aldosterone and renin levels, diuretic screen in urine, response to spironolactone and amiloride, measurement of plasma cortisol level and the urinary cortisol-cortisone ratio, and genetic testing5,79. Test parameters that are considered in differential diagnosis of chronic hypokalemia include blood pressure, acid base equilibrium, serum calcium concentration, 24-hour urine potassium and calcium excretion. 80,81. Hypomagnesemia can lead to increased urinary potassium losses and hypokalemia 79,82. Urine potassium is measured to determine the pathophysiologic mechanism of hypokalemia such as the rate of urinary potassium excretion. Urine electrolyte determination may be assessed by determining the ratio of urine potassium to urine creatinine14. Hypokalemia can co-exist with other diseases and can be a symptom of other diseases. For example, hyperthyroidism, familial or sporadic periodic paralysis are considered when hypokalemia occurs with paralysis 83. Figure 4 5,79,80,83 shows the factors considered in the differential diagnosis of hypokalemia. Determination of the acid-base balance, the blood pressure and urine excretion rate are helpful when making diagnosis of hypokalemia of unknown cause. A common test performed is the urine potassium-creatinine ratio (K/C). Poor potassium intake, gastrointestinal losses, and a shift of potassium into cells are suspected if K/C ratio is <1.5. Barter syndrome, Gitelman syndrome and diuretic use are suspected if K/C ratio is >1.5 but with Metabolic alkalosis and normal blood pressure. Metabolic acidosis with K/C ratio of >1.5 is associated with diabetic ketoacidosis or type 1 or type 2 distal renal tubular acidosis. Also, metabolic alkalosis with a high urine K/C ratio and hypertension have been seen in patients with hyperaldosteronism, Cushing syndrome, congenital adrenal hyperplasia, renal artery stenosis, mineralocorticoid excess 79. Gitelman syndrome (GS), and Bartter syndrome (BS), are some of the diseases closely associated with hyperkalemia.
GS is an inherited renal tubular disorder mostly seen in childhood or early adulthood and it is known to be caused by a mutation in SLC12A3 gene which is a thiazide-sensitive NaCl cotransporter 53. Hypokalemia is one of its classical symptoms and it may account for ~50% of all chronic hypokalemia cases. 84 Other signs include hypotension, metabolic alkalosis, hypocalciuria and hypomagnesemia and hypertrophy of the juxtaglomerular complex with secondary hyperaldosteronism 15,85. Hypokalemia is often within the range 2.4–3.2 mmol/l and patients may have low blood pressure, and complaints of tiredness and increased fatigability. Patients often misdiagnosed of Bartter’s syndrome and futile attempts to treat with indomethacin 86. Gitelman syndrome can be confirmed through Genetic diagnosis by sequence analysis of the SLC12A3 gene to observe if there is a compound heterozygous mutation encoding the thiazide-sensitive sodium chloride co-transporter 87.
BS is like Gitelman syndrome characterized by hypokalemic alkalosis, hypomagnesemia but with hyperreninemic hyperaldosteronemia and normal blood pressure. BS also affects infants or early childhood. Genetic analysis shows mutation in Chloride Channel, Voltage-Sensitive Kb (CLCNKB) gene 53,55. Both BS and GS can be treated with potassium and magnesium oral supplements, e.g. ramipril and spironolactone88.
Hyperkalemia is defined as a serum potassium > 5.5 mEq/L, the normal range is 3.5–5.5 mEq/L for adults5. The range is age dependent and upper limit for young or premature infants, could be up to 6.5 mEq/L. Since the kidneys are the major organs involved in potassium metabolism, any impairment of the kidneys that affects their ability to remove potassium from the blood will lead to hyperkalemia. The condition could be transient (pseudohyperkalemia), for instance large intake of potassium from diet or infusion 16,89. A combination of decreased renal potassium excretion and excessive potassium intake through diet or through infusion will lead to sustained hyperkalemia 18. Prolonged fasting may induce hyperkalemia 90. Factors that contribute to impaired renal potassium excretion include; decrease in distal sodium delivery, decrease in mineralocorticoid level or activity, and abnormal collecting duct function12. Hyperkalemia can be an indicator that cancer patients admitted for an emergency are at high risk for developing a delirium 91. Dysregulation in the expression of WNK genes has been linked to hyperkalemia. For example, KS-WNK1 expression is upregulated in hyperkalemia 92,93.
Another rare but possible cause of hyperkalemia is the shift of potassium from inside the cells to the outside. This shifting of potassium can be caused by several factors such as insulin deficiency or acute acidosis. This condition produces mild-to-moderate hyperkalemia but can exacerbate hyperkalemia induced by high intake or impaired renal excretion of potassium. Hyperkalemia is also a common complication in very low birth weight infants especially in infants with low urinary flow rates during the first few hours after birth 94. Hyperkalemia is a serious and potentially fatal condition that can trigger a heart attack 17. Although many individuals with hyperkalemia are asymptomatic, common symptoms are nonspecific and predominantly related to muscular or cardiac function especially cardiac arrest 13,95,96. Weakness and fatigue are the most common complaints. Potassium homeostasis is also critical to prevent adverse events in patients with cardiovascular disease. Studies have shown that low serum potassium levels of less than 3.5 mEq/L increases the risk of ventricular arrhythmias in patients with acute myocardial infarction (AMI)97. The factors that cause hyperkalemia are shown in Table 2.
The symptoms of hyperkalemia resemble those of other clinical diseases. An understanding of potassium physiology is helpful when approaching patients with hyperkalemia. Factors to be considered during diagnosis of hyperkalemia are shown in Figure 5 5,6,65,79,83,87,98. As mentioned previously plasma potassium concentration are influenced by potassium intake, the distribution of potassium between the cells and the extracellular fluid, and urinary potassium excretion 12,19,61,99.
Pseudohyperkalemia could be as a result of sampling error 17,43. Excess potassium can enter into the blood sample through hemolysis or ischemic muscle cells due to tight tourniquet or hand/arm exercise during the blood-drawing process. Thrombocytosis (platelet count >600,000), leukocytosis (WBC >200,000) or significant hemolysis (serum hemoglobin >1.5 g/dl) can cause hyperkalemia. It is advised to measure plasma potassium if thrombocytosis or severe leukocytosis is present 5,12. Arrhythmia is a feature of hyperkalemia that could be life-threatening and that could also be caused by other diseases 100. It is important to differentiate arrhythmia caused potassium imbalance from by other electrolyte imbalance e.g. Na+, and Ca2+ or drug e.g. digitalis intoxication 101. Chronic Kidney Disease (CKD) and Gordon’s syndrome are some of the diseases closely associated with hyperkalemia.
The main function of the kidneys is to filter wastes and excess water out of the blood to be excreted as urine. The kidney is also the seat of the body’s chemical balance including potassium. Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, the kidney is prompted to excrete more potassium. Hyperkalemia is common in patients with end-stage renal disease as in CKD90. In CKD patients, K+ homeostasis appears to be well maintained until the GFR falls below 15–20 ml/min. The kidney adapts as more nephrons are lost due to CKD by making the remaining nephrons to secrete more K+ 102. This adaptive response is similar to that which occurs due to high dietary K+ intake in normal subjects103. Early stages of renal disease may not show significant abnormalities in potassium activity but renal failure hyperkalemia is a major complication in CKD patients 104. In the presence of renal failure, the proportion of potassium excreted through the gut increases. In patients with CKD, insulin-mediated glucose uptake is impaired, but cellular K+ uptake remains normal89.
This is a rare mineralocorticoid resistance, autosomal dominant diseases which manifests as pseudohypoaldosteronism (PHA). The major features are dehydration, hypertension, severe hyperkalemia, and metabolic acidosis, but with normal glomerular filtration rate. Gordon’s syndrome is characterized by hypertension and hyperkalemia which may be due to enhanced Na+ reabsorption and inhibition of K+ secretion resulting from increased WNK1 expression 105. Intronic deletions in the WNK1 gene result in its overexpression which causes pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia 92. These symptoms have been attributed to over expression of WNK1 105. Gordon’s syndrome can be treated with thiazide diuretics 16,106.
High blood pressure can be influenced by the levels of plasma potassium, low potassium causes hypertension and increasing potassium intake lowers blood pressure 20,107. The blood pressure of people with hypertension is lowered when they are given K+ supplements. However, their blood pressure increases when placed on a low K+ diet and can be worsened by increased renal Na+ reabsorption 99. Hypertension has been one of the symptoms of potassium dependent diseases such as Gordon’s syndrome 106.
Potassium is very important in maintaining cell function such that any imbalance in K+ will have adverse health consequences. As a result, the body has developed numerous mechanisms to make adjustment for any shift in serum K+ homeostasis. All the mechanisms involved are not well understood. However, much has been learned on how the body maintains a proper distribution of K+ within the body. There is also knowledge on how the health effect of K+ imbalance could be managed. For instance, hypokalemia can be managed by reducing potassium losses, replenishing the potassium stores e.g. oral potassium chloride administration, evaluating toxicities and treating of other underlying diseases and determining the root cause to prevent future occurrences. Hyperkalemia like hypokalemia treatment is based on balancing the body’s potassium level. In hyperkalemic condition, the strategy is to reduce the level of potassium in the blood. There are treatment options depending on the potassium level and the physiologic condition of the patient. Dialysis is the definitive treatment of hyperkalemia. However, Intravenous calcium can be used to stabilize the myocardium 108–111. Since Enzymes that are involved in OS also affect potassium activities. An example is heme oxygenase-1 (HO-1) whose expression is increased in the central nervous system (CNS) following an ischemic insult. Understanding the interplay between potassium imbalance and oxidative stress will give more insight into the pathophysiology of human diseases such as cardiomyopathies, neurological syndromes and cancer.
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This research was supported by a grant from the National Institutes of Health (G12MD007581) through the RCMI Center for Environmental Health at Jackson State University.
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There are no conflicts of interest.