"HYPOKALEMIA OR LOW POTASSIUM"

I want to share this research information in "My Journal". This is a very long collection of articles, that explains in great detail, about Hypokalemia or Low Potassium.
It is for anyone who needs help concerning problems dealing with and understanding your potassium levels, why it is so important, what and how it affects many aspects of our bodies. And not just a little problem with what so many call "a little water pill" for their "excess fluid or edema". It is very important that we all take our potassium levels seriously. Too low or too high potassium is both a very serious problem. I know that it is important to eat a potassium rich diet if you have a problem with low potassium, but there is no way to eat enough food containing it if you are dangerously low. It must be taken care of by your doctor. I believe that the information below will help explain in greater detail, from all the different messages that I have received, there is definitely a need to have this explained.

It is one of my health problems that I deal with on a daily basis now for many years, and even more so since this November 2008, after developing Statin-Induced (Zocor and Tricor) Rhabdomyolysis. Just a warning for those who are experiencing leg and muscle pain and spasms, who are on any kind of statin drug. It is a very serious problem that needs to be addressed immediately by your doctor. Mine went on far too long without attention, because my leg and muscle pains were being attributed to my auto-immune disease of SLE Lupus and RA. Because it was neglected for too long it has caused irreversible muscle damage. Just a thought for those who have to take those drugs, please make sure that you are frequently tested with routine blood-work, and taken seriously if you develop muscle pains. I was taking those drugs for the past 7 years, and was receiving blood-workups every 3 months, and I still ended up in the hospital with serious problems that were not caught in time, before the damage was done. Mostly because the extra muscle pain was not being taken seriously for something other than my regular illness.

PLEASE NOTE:

Anyone taking statins who complain of muscle pain...then the statin drug needs to be considered as the possible culprit by the doctors.

Every single drug that is added to our list of medications, all have very serious possible side-effects. The more the meds, the more the problems are compounded, and many times you may end up taking more prescriptions for side-effects of side-effects like I was taking, and in some cases I still am. Research Research Research. It is your best friend in life once you become ill, especially with some odd ball illness that most doctors don't know anything about, and there is very little research funding going to those illnesses. Just my own thoughts and opinions in "My Journal", hoping to be of help to others, as I wished someone had helped me several years ago. Most sincerely and with all my best wishes, thoughts and prayers to all. MandyBlue

I have found that there are many others here in this group, who are having some of the same kind of problems that I have. I am hoping that this collection of articles that were collected, written, and edited by Shawn Kopchu R.N. , will be helpful to all.

HYPOKALEMIA OR LOW POTASSIUM
By Shawna Kopchu R.N.

Hypokalemia refers to a below normal serum potassium concentration. It usually indicates a real deficit in total potassium stores; however, it may occur in patients having normal potassium stores when alkalosis is present (since alkalosis causes a temporary shift of serum potassium into the cells).

Hypokalemia is frequently encountered in clinical medicine and has been estimated to occur in approximately 20% of patients admitted to general internal medicine service. Symptoms may be absent, identified only on routine electrolyte screening, or may range from neuromuscular weakness, rarely progressing to frank paralysis or sudden cardiac death. Usually correction of hypokalemia is not difficult, but if therapy is not appropriate, symptoms may worsen with potentially severe, even lethal, consequences.

Although less than 1% of healthy adults not receiving pharmacologic agents exhibit hypokalemia, the frequency of hypokalemia largely depends on the patient population. The low frequency of hypokalemia is due to both the adequacy of K+ in the typical Western diet and the potent mechanisms for renal K+ conservation in states of K+ depletion. The presence of spontaneous hypokalemia in otherwise healthy adults taking no medicines should suggest the probability of an underlying disease and the need to determine the cause.

Most cases of hypokalemia occur in the setting of specific disease states. Patients receiving thiazide and loop diuretics are at the highest risk, with as many as 50% developing serum K+ levels of less than 3.5 mEq/L. Thiazide diuretics are more likely to cause hypokalemia than loop or osmotic diuretics. Carbonic anhydrase inhibitors, used for refractory glaucoma, produce significant kaliuresis initially, but the ensuing K+ depletion and metabolic acidosis prevent continued K+ loss. Individuals with secondary hyperaldosteronism, whether due to congestive heart failure, hepatic insufficiency, or nephrotic syndrome, may also exhibit hypokalemia. Finally, patients with diseases that alter renal K+ conservation through increased salt delivery are at high risk for hypokalemia.

Consequences of Hypokalemia
Potassium deficiency alters the function of several organs and most prominently affects the cardiovascular system, neurologic system, muscles, and kidneys. These effects ultimately determine the morbidity and mortality related to this condition. Unfortunately, the correlation between degree of potassium deficiency and adverse side-effects is poor, possibly because the occurrence of side-effects is related to both the potassium deficiency and the underlying disease state. Overall, children and young adults tolerate more severe degrees of hypokalemia with less risk of severe side-effects than the elderly.

Cardiovascular
Two major side-effects of hypokalemia affect the cardiovascular system: hypokalemia-related hypertension and hypokalemia-induced ventricular arrhythmias. Both contribute to increased morbidity and mortality.

Hypokalemia contributes to hypertension in many patients but is frequently unrecognized as an important factor that may produce or worsen this serious health problem. Several lines of evidence reveal that potassium deficiency can increase blood pressure. Cross-sectional studies show that low-potassium diets, especially in the presence of a high sodium intake, are linked with the prevalence of hypertension. This association is most marked in African Americans. Epidemiologic and prospective studies confirm this association in both healthy volunteers and in essential hypertensive patients. The antihypertensive effect of thiazide diuretics is reduced by hypokalemia and enhanced by potassium repletion. Finally, blood pressure may be more highly sodium-dependent in the presence of hypokalemia. Thus evidence strongly indicates that hypokalemia contributes to hypertension.

The mechanism of hypokalemia-induced hypertension is not completely clear. One component of this type of hypertension appears to be salt retention. Hypokalemia leads to intravascular volume expansion as a result of renal NaCl retention. Hypokalemia may also potentiate the hypertensive effects of various neurohumoral agents.

Ventricular arrhythmias are a second cardiovascular side-effect of hypokalemia. Several prospective studies show that hypokalemia predisposes patients to the development of a variety of ventricular arrhythmias, including ventricular fibrillation. Patients at the highest risk for arrhythmias, the elderly and those patients with underlying ischemic heart disease, appear to have the highest risk for hypokalemia-related complications. Diuretic-induced hypokalemia is of particular concern because the incidence of sudden death in hypertensive individuals treated with the thiazide diuretic hydrochlorothiazide is greater than that in matched control subjects. The effect is dose-related and is decreased by the concomitant use of potassium-sparing diuretics.

Hormonal
Hypokalemia impairs both insulin release and end-organ sensitivity to insulin, resulting in worsening hyperglycemia in diabetic patients. Hyperglycemia and diabetes mellitus are major public health concerns in industrialized nations. Because increasing evidence suggests that end-organ complications from diabetes mellitus are related to the degree of hyperglycemia, treatment of hypokalemia may decrease the devastating effects of diabetes mellitus.

Muscular
Potassium depletion can result in several muscular-related complications. Hypokalemia can hyperpolarize skeletal muscle cells, impairing their ability to develop the depolarization necessary for muscle contraction. It can also reduce blood flow to skeletal muscles. The reduced blood flow can predispose patients to rhabdomyolysis, especially when vigorous exercise is combined with impaired blood-flow regulation. The combination of these effects frequently leads to muscle weakness, easy fatigability, cramping, and myalgias. Paralysis, although uncommon, can occur in cases of profound potassium deficiency.

Acid-Base
Hypokalemia can profoundly affect systemic acid-base homeostasis through its effects on multiple components of renal acid-base regulation. The most common abnormality is metabolic alkalosis. Hypokalemic metabolic alkalosis results from the effects of hypokalemia on several components of net acid excretion. The most direct effects include stimulation of proximal tubule HCO3 - reabsorption and ammoniagenesis; collecting duct proton secretion, possibly via stimulation of both the gastric (HKalpha1 ) and colonic (HKalpha2 ) isoforms of H+ -K+ -ATPase; and decreasing urinary citrate excretion. Hypokalemia may produce these widespread effects on renal acid-base homeostasis because of intracellular acidification. Hypokalemia also inhibits aldosterone secretion, which possibly minimizes such effects on acid-base homeostasis. In rare cases, severe hypokalemia leads to respiratory muscle weakness and the development of respiratory acidosis. In patients with hypokalemia as a result of renal tubular acidosis, the concomitant development of respiratory acidosis can be life-threatening.

Polyuria
Another complication of hypokalemia is the development of mild polyuria, averaging 2 to 3 liters per day. The polyuria is related to both increased thirst and mild nephrogenic diabetes insipidus. Increased thirst is associated with increased central nervous system levels of angiotensin II, a hormone that, besides its other effects, regulates thirst. Hypokalemia also impairs the kidney’s ability to concentrate the urine maximally. This appears to occur because hypokalemia causes defective activation of renal adenylate cyclase, preventing antidiuretic hormone-stimulated urinary concentration.

Renal Cystic Disease
Hypokalemia, in association with hyperaldosteronism, can lead to renal cystic disease. These cysts appear to arise in the collecting duct epithelium and are frequently associated with interstitial scarring. Correcting the hypokalemia leads to cyst regression. The mechanism of cyst development is unclear. Hypokalemia leads to increased ammoniagenesis and medullary ammonia accumulation, which may activate the complement system. It has been postulated that hypokalemia, by leading to activation of complement in the medullary interstitium, leads to interstitial fibrosis. Consistent with this hypothesis is the observation that bicarbonate supplementation, by inhibiting ammoniagenesis, decreases the interstitial fibrosis associated with hypokalemia; this effect is independent of changes in serum potassium.

Hepatic Encephalopathy
Hypokalemia can contribute to the development, or worsen the symptoms, of hepatic encephalopathy. One toxin that causes hepatic encephalopathy is ammonia, and hypokalemia increases proximal tubule ammoniagenesis. Approximately 50% of proximal tubule ammonia production is returned to the systemic circulation via the renal veins. In hepatic insufficiency, the increased systemic burden of ammonia resulting from increased renal ammoniagenesis can be sufficient to cause the development or worsen the symptoms of hepatic encephalopathy.

Physiology of Potassium Homeostasis
Serum potassium concentration is a balance between intake, excretion, and distribution between the intra- and extracellular space. The average daily potassium intake in a typical Western diet is 70 mEq. Under normal conditions, excretion equals intake, with approximately 90% of potassium excreted in the urine and the vast majority of the remainder in the stool. Distribution of potassium between the intra- and extracellular space plays an important role in potassium homeostasis.

Most potassium is present in the intracellular space. Intracellular potassium averages 120 to 140 mEq/liter, largely as a result of active potassium uptake by Na+ -K+ -ATPase. Approximately 98% of total body potassium is present in the intracellular space. Consequently, small changes in the distribution of potassium between the intra- and extracellular fluid spaces result in proportionally large changes in extracelluar potassium concentration. The large intracellular potassium store functions to minimize changes in extracellular potassium in states of potassium deficiency. Under these conditions, potassium shifts from the intra- to the extracellular fluid, apparently to reduce changes in the transmembrane potassium gradient. With potassium depletion, certain tissues, notably muscle, exhibit a more rapid reduction in intracellular potassium than do others, such as the brain. As a result, small potassium losses minimally affect the serum potassium level. Conversely, the potassium deficit in hypokalemic states that result from potassium loss (excluding pseudohypokalemia and redistribution, as will be discussed below) is very large. For example, a decrease in serum potassium from 3.5 to 3.0 mEq/liter typically indicates a total body potassium deficit of 100 to 300 mEq, and a decrease to 2.0 mEq/liter can indicate a total body deficit of 600 to 800 mEq.

Potassium is present in most foods in varying amounts. Although the typical dietary intake averages 70 mEq/d, there is considerable variation, depending on the dietary preferences of the individual. In the absence of other factors, the body can adapt to a wide range of potassium intake without development of marked hypokalemia. Notably, African Americans commonly eat diets containing less potassium, which may induce a state of physiologic potassium deficiency and contribute to the incidence and severity of hypertension in this population.

The primary mechanism of potassium excretion is the urine. Potassium is freely filtered at the glomerulus, followed by reabsorption of approximately 85% by the proximal tubule and the loop of Henle. Relatively little regulation of potassium reabsorption occurs in these segments, however. Instead, the primary site for renal potassium regulation is the collecting duct. The CCD both secretes and reabsorbs potassium, whereas the outer and inner medullary collecting ducts (OMCD and IMCD, respectively) reabsorb potassium.

At least three cell types are present in the CCD, all of which may contribute to potassium homeostasis. The principal cell is the most numerous cell, comprising 60 to 70% of the CCD, and is believed to be responsible for potassium secretion. Potassium is actively taken up into the cell via a basolateral Na+ -K+ -ATPase and secreted down its electrochemical gradient into the luminal fluid (urine) via an apical potassium channel. Additional evidence indicates that potassium secretion is codependent on Cl secretion. Electrogenic sodium reabsorption generates a lumen-negative charge or voltage. Because this negative charge increases the electrochemical gradient for potassium secretion, the rate of sodium reabsorption also regulates the rate of potassium secretion.

In contrast to the principal cell, the CCD A- and B-type intercalated cells (A cell and B cell, respectively), which comprise the remainder of the CCD, are modeled to reabsorb luminal potassium. Potassium reabsorption occurs through processes different from those of principal cell potassium secretion. An apical H+ -K+ -ATPase secretes protons and reabsorbs luminal potassium, contributing to urinary acidification and potassium reabsorption. In the presence of normal potassium, most reabsorbed potassium is recycled across the apical membrane, resulting in little net potassium transport. In response to potassium deprivation, potassium can exit the cell via a basolateral barium-sensitive transporter, presumably a potassium channel. This provides a sensitive mechanism that allows active potassium reabsorption when necessary.

Recent studies show that the B cell, generally believed to mediate bicarbonate secretion and recovery from metabolic alkalosis, may also contribute to potassium homeostasis. Results from our laboratories and those of others provide strong functional evidence for an apical H+ -K+ -ATPase in this cell. We have also shown that there is coupling of chloride reabsorption by the apical Cl- /HCO3 - exchanger to the apical H+ -K+ -ATPase. Parallel operation of apical H+ -K+ -ATPase and apical Cl- /HCO3 - exchange provide a new model for active KCl reabsorption. Additionally, inhibition of H+ -K+ -ATPase reduces CCD amiloride-insensitive sodium reabsorption, suggesting that sodium can substitute for potassium on the CCD H+ -K+ -ATPase. In hypokalemia, the increased CCD H+ -K+ -ATPase activity, in combination with sodium substituting for potassium on the H+ -K+ -ATPase, could lead to net NaCl reabsorption, volume expansion, and the increased blood pressure that is observed clinically.

The OMCD and IMCD do not transport potassium under normal conditions, but in response to hypokalemia or potassium deficiency can reabsorb potassium. This appears to occur via mechanisms similar to the CCD A cell, e.g., luminal potassium uptake by an apical H+ -K+ -ATPase and basolateral potassium exit via a basolateral potassium channel. As noted previously, at least two isoforms of H+ -K+ -ATPase are present in the collecting duct: HKalpha1 and HKalpha2. HKalpha1 may be regulated to a greater extent by hypokalemia than HKalpha2 in the CCD, whereas the opposite appears to be true in the OMCD.

Despite the presence of active potassium reabsorptive transporters in the CCD, OMCD, and IMCD, the urinary potassium level is generally not lower than 15 to 20 mEq/liter. This may reflect both water reabsorption, which exceeds potassium reabsorption, and persistent potassium secretion in the CCD.

Little potassium is excreted in the stool under normal conditions because of a low stool volume and a low stool potassium concentration. Conditions that increase stool potassium concentration, such as chronic renal failure and hyperkalemia, or stool volume, such as diarrhea, increase fecal potassium excretion. Chronic renal failure can cause adaptive changes in stool potassium content, such that as much as 20 to 30 mEq/d can be excreted by this route. Decreases in stool potassium content do not materially affect the response to hypokalemia because the basal level of stool potassium excretion is normally small.

Etiological Factors Associated With Hypokalemia
Causes of Hypokalemia
The accurate treatment of hypokalemia requires correct identification of the cause. Hypokalemia can be associated either with normal or decreased total body potassium content. Normal total body potassium with hypokalemia is a result of potassium redistribution from the extracellular to the intracellular space. Total body potassium depletion can result from either renal or extrarenal potassium losses. We suggest that the clinician evaluating a patient with hypokalemia consider four broad groups of etiologies: pseudohypokalemia, redistribution, extrarenal potassium loss, and renal potassium loss.

Pseudohypokalemia
Abnormal white blood cells, if present in large enough numbers, can take up extracellular potassium when stored for prolonged periods at room temperature, resulting in a low measured plasma potassium level. The apparent hypokalemia is an artifact of the storage procedure and is referred to as “pseudohypokalemia” . The most common underlying disease state is acute myelogenous leukemia. Rapid separation of the plasma or storing the sample at 4?C confirms the diagnosis, avoids this artifact, and prevents inappropriate treatment.

Redistribution
More than 98% of total body potassium is present in the intracellular fluid, predominantly in skeletal muscle cells, enabling small changes in the distribution of potassium to alter the extracellular concentration markedly. Certain hormones, particularly insulin, aldosterone, and sympathomimetics, are the most common cause of redistribution-induced hypokalemia. Insulin activates Na+ -K+ -ATPase, which results in active potassium uptake . Acute insulin administration produces rapid potassium shifts from the extra- to intracellular space, resulting in hypokalemia. This problem is most frequently encountered in the treatment of diabetic ketoacidosis. Insulin-induced redistribution of potassium is the physiologic principle underlying the administration of insulin with glucose to patients with hyperkalemia. In contrast to acute insulin administration, chronically high insulin levels, as occur in insulinomas, do not typically cause hypokalemia; the mechanism of this “escape” is unknown. The decreased end-organ responsiveness to insulin in adult-onset diabetes may contribute to the hyperkalemia frequently seen by altering the distribution of potassium between the intra- and extracellular space.

A second, clinically common cause of potassium redistribution is aldosterone. Aldosterone induces cellular uptake of potassium through a variety of effects, but much more slowly than insulin. Aldosterone stimulates the production of Na+ -K+ -ATPase, which results in increased enzyme activity and the transport of potassium from the intracellular to extracellular space. In addition, as will be discussed below, aldosterone also regulates renal potassium transport. Thus hyperaldosteronism causes hypokalemia as a result of the combined effects of redistribution and stimulation of renal potassium clearance.

The final major hormonal cause of potassium redistribution includes sympathomimetic agents, beta2 -adrenergic agonists, dopamine, dobutamine, and theophylline. The first three agents directly stimulate the cellular uptake of potassium and also stimulate insulin release, whereas theophylline indirectly stimulates potassium uptake. Sympathomimetic-induced redistribution leading to hypokalemia is important in acute myocardial ischemia and acute asthma therapy. Myocardial ischemia commonly increases sympathetic tone, whether as a direct result of the ischemia, decreased cardiac output, or from either the pain or the anxiety related to the ischemia. Cellular potassium redistribution leading to hypokalemia can then increase the risk of ventricular arrhythmia and sudden death. Treatment of the asthma patient with beta-adrenergic agonists or theophylline can lead to potassium redistribution, hypokalemia, and impairment of respiratory muscle contractile ability. Patients may develop CO2 retention, or, even more seriously, decreased wheezing, as a result of decreased air movement, which might be misinterpreted as an overall improvement in the patient’s condition. Another clinical concern is premature labor therapy involving beta-agonists. These patients frequently do not have oral intake for prolonged periods, providing a setting for the development of severe hypokalemia.

Hypokalemia as a result of potassium redistribution can also occur from acute anabolic states. Cells contain approximately 130 mEq/liter of potassium; consequently, stimulation of either cell hypertrophy or cell production can cause rapid movement of potassium from the extra- to the intracellular space. Rapid cell production can occur in acute leukemia and high-grade lymphomas. Acute stimulation of cell production can result from granulocyte macrophage colony-stimulating factor treatment of refractory anemia or the initial treatment of pernicious anemia with vitamin B12. The resultant cell production can cause acute hypokalemia and in some individuals has resulted in arrhythmias and sudden death.

Rarely, hypokalemia secondary to redistribution with enhanced cellular uptake can be a result of hypokalemic periodic paralysis. Both familial and sporadic cases have been reported. Most hereditary cases follow an autosomal dominant distribution, although an X-linked recessive form has been documented. In Asians there is a high frequency of this condition associated with thyrotoxicosis. Attacks frequently commence during the night or the early morning and are characterized by flaccid paralysis of all extremities, which may persist from 6 to 24 h. A genetic defect in a dihydropyridine-sensitive calcium channel has been determined to cause certain cases of this disorder. Carbonic anhydrase inhibitors (acetazolamide 250 mg four times daily), beta blockers, or spironolactone may prevent attacks.

Finally, hypokalemia has been reported in connection with chloroquine and barium intoxication. The latter effect can be explained by the known action of barium to block potassium channels and, hence, cellular potassium exit.

Non Renal Loss
Both the skin and the gastrointestinal tract can transport significant amounts of potassium. Under normal conditions, net fluid loss from these organs is small, limiting net potassium loss. Occasionally, in cases such as prolonged exertion in hot, dry environments or chronic diarrhea, severe potassium loss can occur, leading to hypokalemia. In most of these cases, intravascular volume depletion is present also, leading to secondary hyperaldosteronism, stimulation of renal potassium excretion, and further worsening of the potassium deficit.

Prolonged loss of gastric contents, whether from vomiting or nasogastric suctioning, can lead to hypokalemia. A small part of this potassium loss is direct because these body fluids contain 5 to 8 mEq/liter potassium. More importantly, concomitant alkalosis and intravascular volume depletion contribute to renal potassium loss. Metabolic alkalosis results in bicarbonaturia, which increases potassium excretion both directly, as a cation to balance the negative charge of bicarbonate ions, and indirectly, through stimulation of urinary sodium excretion, leading to worsening of intravascular volume depletion and stimulation of the renin-angiotensin-aldosterone system. In addition, potassium reabsorption by the collecting duct is affected by acid-base status. Thus metabolic alkalosis increases renal potassium excretion by increasing potassium secretion and probably by direct suppression of potassium reabsorption.

Diarrhea, whether secretory or as a result of laxative abuse, can cause profound gastrointestinal potassium loss. Patients with laxative abuse may deny the condition because of over-concern about body image and may also abuse diuretics. If magnesium- or phosphate-containing cathartics, such as magnesium citrate or sodium phosphate, are suspected, direct measurement of these compounds in the stool can confirm the diagnosis.

Gastrointestinal Loss
■Diarrhea
■Laxative Abuse
■Prolonged Gastric Suction
■Protracted Vomiting
■Villose adenoma
Renal Loss
Causes of renal potassium loss
Drugs

Many medications can cause renal potassium wasting, including diuretics and some antibiotics. Both thiazide and loop diuretics increase urinary potassium excretion; when factored for their natriuretic (Sodium wasting) effect, thiazide diuretics are more potent kaliuretic (Potassium wasting) agents. In part this is because loop diuretics have a shorter pharmacologic half-life, enabling renal potassium conservation during periods between drug administration, but may also reflect their site of action in the distal convoluted tubule with secondary effects on flow to the primary site of potassium secretion in the CCD. All diuretics, except the potassium-sparing diuretics, induce potassium-wasting by increasing CCD luminal flow rate, luminal sodium delivery, and luminal electronegativity, which are the primary determinants of potassium secretion by the CCD. They may also induce intravascular volume contraction, resulting in secondary hyperaldosteronism and further stimulation of renal potassium secretion. The incidence of diuretic-induced hypokalemia is both dose- and treatment duration-related.

Antibiotics can increase urinary potassium excretion by a variety of mechanisms. High-dose penicillin and some penicillin analogues, such as carbenicillin, oxacillin, and ampicillin, increase distal tubular delivery of a non-reabsorbable anion, thereby increasing urinary potassium excretion. Cisplatin is another drug that may induce hypokalemia via an increase in renal potassium excretion. Polyene antibiotics, such as amphotericin B, create cation channels in the apical membrane of collecting duct cells, which increases potassium secretion and results in potassium wasting.

Diuretics

■Thiazide Diuretics
■Loop Diuretics
■Osmotic Diuretics
Antibiotics

■Penicillin and Penicillin analogues
■Amphotericin B
■Aminoglycosides**
Hormones

Endogenous hormones are very important causes of hypokalemia. Aldosterone is perhaps the most important hormone regulating total body potassium homeostasis, and excess aldosterone production or effect frequently leads to hypokalemia. The CCD is the primary site in the kidney where aldosterone regulates potassium transport, and the CCD principal cell is the CCD cell responsible for potassium secretion. Aldosterone increases principal cell apical sodium conductance, basolateral Na+ -K+ -ATPase activity, and electrogenic sodium absorption in the CCD. These effects increase the net luminal-negative charge or transepithelial voltage, which increases the electrochemical gradient for potassium movement from the principal cell cytoplasm to the luminal fluid. Thus aldosterone, via actions on apical Na+ channels and basolateral Na+ -K+ -ATPase, increases CCD principal cell potassium secretion. Although potassium reabsorption can occur in the OMCD and IMCD, the reabsorptive capacity of these segments, particularly with normal Na intake, is less than the rate of potassium secretion by the CCD. Thus the net effect of aldosterone is to enhance renal potassium clearance.

Hyperaldosteronism can be either primary or secondary. Primary hyperaldosteronism results in cases of hypertension, predominantly because of the sodium-retaining effects of aldosterone, but the associated hypokalemia may also contribute by sensitizing the vasculature to neurohumoral regulators of blood pressure. Because angiotensin II regulates adrenal gland aldosterone synthesis, conditions involving elevated angiotensin II levels will typically involve hyperaldosteronism. This may occur in a variety of conditions, such as decreased oral intake, diuretic use, vomiting, or diarrhea. Activation of the renin-angiotensin-aldosterone system, as may occur in malignant hypertension, renovascular hypertension, and renin-secreting tumors, can also lead to secondary hyperaldosteronism with subsequent hypokalemia. The secondary activation of the renin-angiotensin-aldosterone system suggests that potassium redistribution significantly contributes to the hypokalemia.

Rarely, genomic defects lead to excessive aldosterone production. In glucocorticoid-remediable aldosteronism, an adrenocorticotropin (ACTH)-regulated gene is linked to the coding sequence of the aldosterone synthase gene, the rate-limiting enzyme for aldosterone synthesis. Aldosterone synthase is no longer regulated by the renin-angiotensin system, and excessive aldosterone production ensures. In congenital adrenal hyperplasia, there is the congenital absence of either 11beta-hydroxylase or 17alpha-hydroxylase, resulting in excess hypothalamic corticotropin-releasing hormone (CRH) secretion and persistent adrenal synthesis of 11-deoxycorticosterone, a potent mineralocorticoid. This condition can be recognized by the associated effects on sex steroid production. 11beta-hydroxylase deficiency results in increased androgen production, leading to early virilization of men and women. In contrast, 17alpha-hydroxylase deficiency inhibits sex hormone metabolism, leading to incomplete development of sexual characteristics.

Under rare conditions, glucocorticoids function as mineralocorticoids, causing hypokalemia and hypertension. Glucocorticoids, such as cortisol, have a high affinity for the mineralocorticoid receptor but are normally prevented from binding to it because the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSDH) converts cortisol to cortisone, which does not bind to the mineralocorticoid receptor. Some drugs, such as glycerrhetinic acid (found in carbenoxolone, chewing tobacco, and licorice), inhibit 11beta-HSDH, allowing cortisol to exert mineralocorticoid-like effects in the distal nephron. Infrequently, circulating cortisol can exceed the metabolic capacity of 11beta-HSDH and cause hypokalemia. This can occur either in severe cases of Cushing’s disease or in the ectopic ACTH syndrome.

Magnesium depletion
Concomitant magnesium deficiency may prevent correction of hypokalemia. This is particularly true with diuretic-induced hypokalemia and in certain cases of aminoglycoside- and cisplatin-induced potassium wasting, hypokalemia associated with lysozymuria in acute leukemia, and in individuals with Gitelman’s syndrome (see below). Supplementation with oral magnesium supplements, may serve to correct both the magnesium and potassium deficiency.

Intrinsic renal defects
Intrinsic renal defects leading to hypokalemia are rare but have led to important advances in our understanding of renal solute transport. In 1962, Bartter described the association of hypokalemia, hypomagnesemia, hyperreninemia, and metabolic alkalosis. Recent studies show that these patients can be divided into two groups now known as either Bartter’s syndrome or Gitelman’s syndrome. Patients with Bartter’s syndrome are hypercalciuric and present at an early age with severe volume depletion. This condition appears to be a result of defects in either the renal Na-K-2Cl cotransporter gene, NKCC2, or the ATP-sensitive potassium channel, ROMK, both of which are necessary for loop of Henle sodium reabsorption. Gitelman’s syndrome features hypocalciuria, hypomagnesemia, and milder clinical manifestations and presents at a later age. This syndrome appears to be a result of mutations in the thiazide-sensitive NaCl cotransporter. Both Bartter’s syndrome and Gitelman’s syndrome are associated with hypotension and intravascular volume depletion due to renal sodium-wasting. In contrast, Liddle’s syndrome is associated with hypertension, hypokalemia, metabolic alkalosis, and suppressed renin and aldosterone levels. This condition appears to be a result of defects in the CCD principal cell apical sodium channel, ENaC, leading to an increased open probability, excessive sodium reabsorption, and subsequent volume expansion, hypertension, and suppression of renin and aldosterone. Renal potassium wasting occurs because increased CCD sodium reabsorption leads to increased luminal electronegativity and an increased electrochemical gradient for potassium secretion.

Bicarbonaturia
The last major cause of renal potassium wasting is bicarbonaturia. Bicarbonaturia can result from either metabolic alkalosis, distal renal tubular acidosis, or treatment of proximal renal tubular acidosis. In each case, distal tubular bicarbonate delivery increases potassium secretion. Certain cases of distal renal tubular acidosis may reflect primary defects in potassium reabsorption.

Other less common causes

■Cisplatin
■Carbonic anhydrase inhibitors
■Toluene*
■Leukemia
■Diuretic phase of acute tubular necrosis
■Intrinsic renal transport defects
■Bartter’s syndrome
■Gitelman’s syndrome
■Liddle’s syndrome
■European Licorice Abuse
*Toluene exposure, which can result from sniffing certain glues, can also cause hypokalemia, presumably by renal potassium wasting.

**Aminoglycosides can cause hypokalemia either in the presence or absence of overt nephrotoxicity. The mechanism is not completely understood but may relate to stimulation of magnesium depletion or direct inhibition of potassium reabsorption. However, most antibiotics do not cause hypokalemia, and some, such as trimethoprim and pentamidine, can cause hyperkalemia by inhibition of apical sodium channels in the CCD.

Correction
The risks associated with hypokalemia must be balanced against the risks of therapy when the appropriate approach to the patient is determined. Usually, the primary short-term risks are cardiovascular, and the most important is the proarrhythmogenic effect of hypokalemia. In contrast, the primary risk of overaggressive replacement is the development of hyperkalemia with resultant ventricular fibrillation. Occasionally, incorrect therapy of hypokalemia can lead to paradoxical worsening of the hypokalemia.

Conditions requiring emergent therapy are rare. The classic causes include severe hypokalemia in a patient preparing to undergo emergent surgery, particularly in patients with known coronary artery disease or on digitalis treatment, and the patient with an acute myocardial infarction and significant ventricular ectopy. In such cases, administration of 5 to 10 mEq of KCl over 15 to 20 min may be used to increase serum potassium to a level above 3.0 mEq/liter. This dose can be repeated as needed. Close, continuous monitoring of the serum level and the electrocardiogram (ECG) are necessary to reduce the risk of hyperkalemia.

In most other conditions, the choice of parenteral versus oral therapy is dependent on the ability of the patient to take oral medication and the ability of the GI tract to function appropriately. In many cases, such as myocardial infarction, paralysis, and hepatic encephalopathy, the patient may be unable to take oral potassium safely or questions may exist about the speed of GI tract absorption. In these cases, KCl can be given intravenously. When given via the intravenous (IV) route, replacement can be given safely at a rate of 10 mEq KCl per hour. One study has found that 20 mEq KCl per hour causes the serum potassium level to increase by an average of 0.25 mEq/L per hour. If more rapid replacement is necessary, then 40 mEq per hour can be administered through a central catheter with continuous ECG monitoring. However, replacement therapy should be administered orally if possible.

The parenteral fluids used for potassium administration can affect the response. In nondiabetic patients, IV dextrose increases serum insulin levels, which can cause redistribution of potassium from the extra- to the intracellular space. As a result, providing KCl in glucose solutions such as D5 W can paradoxically lower serum potassium levels. In most cases, parenteral KCl should be provided in normal saline. If large concentrations of KCl are added to the parenteral fluid, then KCl might be administered in half normal saline to avoid administration of a hypertonic solution.

Usually hypokalemia can be treated successfully with oral therapy. Patients with diuretic-induced hypokalemia should be re-evaluated to reconsider the need for diuretics. If continual use is required, assessment of sodium intake should be preformed. Excessive sodium intake accentuates diuretic-induced hypokalemia. If this is not the case concomitant use of the potassium-sparing diuretics amiloride, triamterene, and spironolactone may be considered. When oral replacement therapy is required, KCl is the preferred drug in all patients except those with metabolic acidosis. In the latter condition, either potassium bicarbonate or potassium citrate should be used. The chloride salt of potassium minimizes renal potassium losses. If indicated for other reasons, beta blockers or angiotensin-converting enzyme inhibitors can assist in maintaining potassium levels.

Finally, hypomagnesemia can lead to renal potassium wasting and refractoriness to potassium replacement. In these patients, correction of the hypokalemia does not occur until the hypomagnesemia is corrected. Patients with diuretic-induced hypokalemia, unexplained hypokalemia, or diuretic-induced hypokalemia should have their serum magnesium levels checked and magnesium replacement therapy begun if indicated.