Potassium Homeostasis and Hypokalemia

Potassium Homeostasis and Hypokalemia

0031-3955/87 $0.00 Pediatric Nephrology + .20 Potassium Homeostasis and Hypokalemia Michael A. Linshaw, MD* Potassium, the most abundant cation in...

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0031-3955/87 $0.00

Pediatric Nephrology

+ .20

Potassium Homeostasis and Hypokalemia Michael A. Linshaw, MD*

Potassium, the most abundant cation in intracellular fluid, plays a key role in' several fundamental cellular homeostatic processes. Regulatory mechanisms combine to maintain the total body potassium at approximately 50 to 55 mEq per kg of body weight. As a major constituent of the intracellular osmotic pressure, potassium contributes significantly to the control of intracellular volume. The ratio of intra- to extracellular potassium helps determine the electrical properties of excitable tissues such as muscle and nerve and nonexcitable tissue such as transporting epithelia. Potassium also modifies the intracellular pH and the hydrogen ion activity in the cell and plays a major role in cellular metabolism, affecting, for example, protein, nucleic acid, and glycogen synthesis. During growth, potassium intake must exceed excretion as new cells accrue with a high potassium content. Although there is a steady, roughly linear increase in total body potassium content of approximately 0.08 gm per kg per year of gross body weight over the first 6 to 8 years of life (Figure 1), careful studies detailing accretion rates and changes in positive potassium balance during growth are not available. Ultimately, the body enters a balanced state where potassium intake equals excretion. Daily potassium requirements are estimated at approximately 2.0 mEq per 100 Kcal of energy requirements throughout most of childhood. 90 An adult's dietary intake varies from approximately 50 to 150 mEq per day. Potassium is readily absorbed from the gastrointestinal tract, and the body cells, particularly those in skeletal muscle, can temporarily accommodate excess potassium and help maintain the serum potassium levels between 3.5 and 5 mEq per liter. . About 98 per cent of potassium is present in cells, particularly skeletal muscle. These cells provide a large sink to accommodate potassium entering the extracellular fluid. Variations in potassium intake lead to adjustments in excretion, the major route of which is through the kidney and to a much lesser extent the bowel. Adaptations can occur in a matter of hours to days *Professor, Department of Pediatrics; Chief, Section of Pediatric Nephrology, The University of Connecticut Health Center, School of Medicine, Farmington, Connecticut

Pediatric Clinics of North America-Vol. 34, No.3, June 1987

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Figure 1. A, Average body potassium concentrations of males and females as a function of chronologie age (grams/kilogram of gross body weight). 8, Change in male and female potassium concentrations in relation to growth (as indicated by weight gain). (From Anderson EC, Langham WH: Average potassium concentration of the human body as a function of age. Science 130:713-714, 1959; with permission.)

to facilitate the renal excretion of potassium when required. The colon also excretes potassium and responds to stimuli that alter potassium transport but to a much lesser extent than the kidney. This latter source of potassium excretion is probably the result of increased K+ secretion and becomes more important during states of reduced renal function. 83• Adaptive responses of both tissues to chronic K loading include an increase in the

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basolateral membrane surface area and an increase in (Na+ + K+) ATPase activity in the sensitive tissues (surface mucosal cells in the colon and principal cells in the collecting tubule). Aldosterone appears to be an important mediator of this adaptive response. 60 While the kidney is the primary organ responsible for maintaining chronic potassium balance, the kidney is unable to excrete an acute potassium load as efficiently as when chronic adaptive mechanisms have already been stimulated. In the absence of such adaptations, nonrenal factors will contribute significantly to maintaining potassium balance. Following an acute potassium load, approximately one half the potassium appears in the urine over the first 4 to 6 hours (Figure 2). If all the unexcreted potassium from this load were to remain in the extracellular fluid, life-threatening hyperkalemia might develop. However, extrarenal mechanisms stabilize the extracellular fluid potassium concentration by allowing storage of excess potassium in cells until the kidneys can excrete the entire' potassium load. 34, 37, 38

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Figure 2. Extrarenal distribution of an acutely administered intravenus potassium load (0.75 mEq per kg) in healthy subjects. During the first 4 to 6 hours following administration of KCl, approximately 40 per cent was excreted. If all of the retained potassium remained in the extracellular fluid compartment, marked hyperkalemia would have ensued. This did not Occur since over 70 to 80 per cent of the retained potassium was translocated into cells. (From DeFronzo RA, Bia M: Extrarenal potassium homeostasis. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology, New York, Raven Press, 1985, pp 1179-1206; with permission.)

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POTASSIUM HOMEOSTASIS

Nonrenal Factors Involved in Potassium Homeostasis Several extrarenal factors control potassium homeostasis (Table 1) and have been recently reviewed. 49 , 139 Hormonal Insulin lowers plasma potassium by causing potassium to shift from extracellular to intracellular fluid 34, 36, 37 and can be shown to help dissipate the effect of an acute exogenous potassium load. Infusions of KCI sufficient to increase serum K+ concentration 1 mEq per I or more stimulate insulin secretion from the pancreas. 34 Pancreatectomized dogs tolerate the KCl poorly, but potassium tolerance can be restored by providing exogenous insulin. 34 Insulin contributes to K+ regulation even when increases in plasma K+ are relatively small. In dogs, DeFronzo found that when KCl was infused to increase the serum K+ by about 0.6 mEq per 1, peripheral insulin levels did not rise. However, adding somatostatin, an inhibitor of insulin secretion, to the infusion caused circulating basal insulin levels to fall nearly 50 per cent and serum K+ to rise substantially. The rise in serum K+ above control was abolished by infusing insulin along with somatostatin. 37 Similarly, in humans somatostatin caused a rise in serum K+ that could be reversed by providing sufficient exogenous insulin to maintain basal insulin levels. Moreover, adult onset diabetics who have normal or elevated fasting insulin levels also develop hyperkalemia when basal insulin secretion is inhibited by somatostatin, but juvenile diabetics who lack insulin do not develop somatostatin induced hyperkalemia (Figure 3). These results emphasize the role of basal insulin secretion in maintaining plasma potassium within the normal range. 34 Insulin can stimulate the cellular uptake of potassium in muscle (skeletal and cardiac), adipose and hepatic tissue 27 , 88, 104, 141, 142 independent of glucose metabolism. Insulin rapidly hyperpolarizes the interior of the Table 1. Nonrenal Factors Influencing Potassium Homeostasis FACfORS INCREASING SERUM [K+]

Hormones

Acid-base status Extracellular fluid tonicity Drugs

Alpha catecholamines Decreased insulin and hyperglycemia Decreased aldosterone Acidosis Hyperosmolality Beta-adrenergic antagonists Propranolol Butoxamine Alpha-adrenergic agonists Phenylephrine Mannitol (hyperosmolality) Digitalis Succinylcholine Arginine

FACfORS DECREASING SERUM [K+]

Beta 2 catecholamines Insulin Aldosterone Alkalosis Beta 2 agonist Epinephrine Isoproterenol Salbutamol Terbutaline Barium

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cell, stimulates (Na+ = K+) ATPase 84 , 86, 141, 144 and also stimulates a sodiumhydrogen exchange system in the plasma membrane. 85 Additional mechanisms that may affect K+ uptake are not presently defined, The important point is that (1) insulin secretion, stimulated by hyperkalemia, blunts the full effect of a KCI load on serum K+ and (2) a KCI load insufficient to increase circulating peripheral insulin levels nevertheless is still apparently regulated by basal insulin. Catecholamines. Catecholamines also stimulate the intracellular uptake of potassium (Figure 4). In healthy human volunteers, a KCI infusion sufficient to raise the serum potassium by 0.5 or more mEq per I leads to increased K+ excretion. In response to epinephrine, the increased K+ excretion can be substantially inhibited, and yet serum K+ increases only slightly because intracellular uptake of potassium is stimulated by epinephrine. 35, lOS The protective effect of epinephrine on serum K+ occurs in nephrectomized animals. 59a Extrarenal potassium control is impaired in adrenalectomized dogs and can be restored by providing physiologic amounts of epinephrine. 8 Propranolol, a beta receptor blocker, abolishes both the renal and extrarenal effect of epinephrine on potassium 35, 105 and actually causes a small increase in serum K+. 35 Epinephrine appears to exert its cellular effect by binding a beta 2 adrenergic receptor, stimulating adenylate cyclase, increasing intracellular conversion of ATP to cyclic 3-5 AMP which in turn activates the sodium pump. 26, 102 Mineralocorticoids. Mineralocorticoids appear to exert a significant effect on extrarenal potassium balance. 9 , 32, 33, 36 In patients with hypoaldosteronism, administration of mineralocorticoid causes serum potassium to fall without necessarily an increase in renal or fecal potassium. 33, 47 In nephrectomized rats, adrenalectomized animals tolerated an acute potas-

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Epinephrine

Figure 4. Effect of epinephrine on the increment in serum potassium induced by an intravenous potassium load. Changes in serum potassium with potassium loading in the absence of epinephrine, denoted by closed circles, and in the presence of epinephrine, by open triangles. Values are mean ± SEM in 5 subjects. Overall probability of the difference between treatments was 0.01 by repeated measure analysis. (From Rosa RM, Silva P, Young JB, et al: Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 302:431-434, 1980; with permission.)

sium load poorly and developed significantly more hyperkalemia than controls. This potassium intolerance could be attenuated by administering mineralocorticoid to the adrenalectomized animals. 3, 9, 36

Acid-Base Balance Acidosis tends to increase and alkalosis to decrease serum potassium whether or not the acid base derangement is metabolic or respiratory in origin. The relationship between serum potassium and acidosis is complex and quite variable, with a variety of factors contributing to the final serum K+ concentration. The following discussion summarizes some observations and current hypotheses to explain this relationship. The type of acidosis. Metabolic acidosis exerts a more profound effect on potassium (a rise of 0.5 to 1.2 mEq per 1) than respiratory acidosis (a rise of only 0.1 to 0.3 mEq per liter).34 This may be because in respiratory acidosis the increase in PC0 2 leads to an increase in intracellular PC0 2 that forms carbonic acid and in tum generates H+ + HC03-. Since the cell interior accumulates an ion and a cation, there is no charge separation and thus no drive for potassium to move from cell to extracellular fluid. 34, 55 Similarly, alkalosis tends to cause a decrease in potassium. In metabolic alkalosis, the movement of intracellular hydrogen to the extracellular fluid occurs largely from proteins, which being imperme~nt and

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POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

negatively charged, will help drive the movement of potassium into the cell with a substantial decrease in serum potassium concentration. In respiratory alkalosis, the drop in PC02 generates a move of intracellular CO 2 to the extracellular fluid. The compensatory low serum bicarbonate developing in respiratory alkalosis is associated with some loss of cellular hydrogen ion with a resultant electrochemical driving force favoring potassium entry to the cells and a decrease in potassium concentration. 55

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Infusions of acid with inorganic anions such as chloride (HC1, NH 4 Cl) will lead to marked hyperkalemia probably because as hydrogen enters the cells, chloride, or another relatively nonpermeant anion remains in the extracellular fluid, creating an electrochemical gradient favoring potassium loss from cells. If the infusion is with an organic acid such as lactic acid, beta hydroxybutyric acid or methylmalonic acid, the organic anions may cross th~ cell membrane readily, accompanying the hydrogen ion and maintaining electrical neutrality with no resultant driving force for potassium egress from the cell (Figure 5).95, 103

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Changes in plasma bicarbonate concentration. There is evidence that serum bicarbonate affects serum potassium independent of the extracellular fluid pH since lowering bicarbonate by acid infusion along with a concomitant decrease in PC02 to maintain the pH constant leads to an increase in serum potassium. Conversely, bicarbonate infusion in the face of constant pH leads to a decrease in serum potassium concentration. 43• 44, 67 The duration of the acidosis. Duration is important since hyperkalemia tends to occur after the most marked changes in blood pH and bicarbonate have already resolved. In dogs following an acid infusion, serum potassium rises slightly as serum pH and bicarbonate drop, and continues to rise substantially even after pH and bicarbonate begin to recover (Figure 6), as though the change in potassium is related to the intracellular buffering process. 111, 120, 125 If intracellular stores of potassium are depleted, as often occurs in the diabetic with ketoacidosis, the effect of hydrogen to increase serum potassium concentration may be offset by the decrease in total body and intracellular potassium. Sodium Potassium ATPase The sodium pump is the major factor responsible for maintaining the distribution of potassium across the membrane away from electrochemical equilibrium. Acute impairment of the pump, such as with digitalis overdose, may cause marked hyperkalemia. 100 More chronic perturbations of the pump usually cause little change in potassium because of increased renal potassium excretion. Extracellular Fluid Hypertonicity EFH from mannitol or glucose (as in the diabetic) may induce hyperkalemia by abstracting water from cells, thereby increasing the intracellular potassium concentration and thus the diffusion of potassium from the cell. 82, 87 Glucose mediated hyperkalemia is particularly prominent in the absence of insulin and aldosterone,52 but may also occur in diabetics with normal plasma aldosterone. 92 Hyperosmolality can also induce hyperkalemia in the

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POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

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absence of changes in plasma insulin. Volunteers were subjected to infusions of isotonic saline, isotonic mannitol, or hypertonic mannitol. The isotonic infusions caused no change in plasma osmolality and induced no change in plasma' potassium, but when plasma osmolality increased nearly 20 mOsm per kg from hypertonic mannitol infusion, plasma potassium increased 0.5 mEq per 1 in the absence of changes in insulin levels and despite an actual increase in potassium excretion. 22. 97 Renal Factors Influencing Potassium Homeostasis

General Considerations After an acute potassium load, extrarenal factors modulate and delay to some extent the renal excretion of K+ by stimulating cellular K+ uptake. However, it ultimately falls on the kidney to excrete the excess potassium. A brief review of renal potassium handling follows. Renal Handling of Potassium Since the potassium concentration in plasma is low, the amount filtered is very low compared to that of sodium. If the GFR is 120 m} per min and potassium concentration is 3.5 to 5 mEq per 1, the amount of filtered potassium is some 600 to 860 mEq per day, easily enough to allow excretion of the dietary potassium. When GFR decreases to about 10 per cent of normal, filtration alone may be insufficient to allow for excretion of the dietary K+. Adaptive tubular processes facilitate potassium excretion as the GFR decreases; in fact, tubular secretory mechanisms are primarily responsible for the excretion of potassium. Potassium handling by the kidney has been summarized clearly in several recent reviews. 45. 49. 106. 139 Potassium is freely filtered by the glomerulus. Net reabsorption of about 80 per cent of the filtered potassium occurs in the proximal tubule with potassium moving both through the cells by active transport and between the cells by passive forces. 139 The reabsorption of potassium in the proximal tubule is influenced by fluid reabsorption. Decreasing fluid reabsorption or inducing fluid secretion by perfusing the tubule with mannitol leads to potassium secretion in this segment. 19 In Fanconi syndrome, amino acids, glucose, phosphorus, and often bicarbonate wasting occur from reduced reabsorption in the proximal tubule. Hypokalemia is probably related to defective proximal tubule potassium reabsorption as well as increased distal potassium secretion driven by increased sodium and bicarbonate delivery, increased fluid loss, and secondary hyperaldosteronism. Potassium appears to be secreted in the thin descending limb of Henle, but net reabsorption of about 10 per cent of the filtered potassium occurs along the thick ascending loop of Henle. 49 Here, luminal K+ is reabsorbed by an electrically neutral cotransport system involving a sodium, a potassium and two chloride ions. 59 (Na+ + K+) ATPase drives the process by extruding sodium across the basolateral membrane, thus providing a diffusion gradient for sodium from lumen to cell. Potassium can diffuse back into the lumen via a conductive pathway providing potassium ions for continued cotransport of sodium and chloride. It has been proposed that the defect in Bartter's syndrome resides along this nephron segment. 51 Potassium reabsorption can be decreased or blocked by removing any of these ions from the lumen, by replacing chloride with bicarbonate or a nonreabsorbable anion, or

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adding furosemide to the lumen. The high luminal potassium conductance is affected by several factors. It can be increased by ADH and by a high potassium diet, and decreased by acidifying the environment of the cells. 49 Potassium concentration in the interstitium and papillary tip is considerably higher than in plasma and thus by countercurrent exchange between loops of Henle, K+ is trapped in the medulla. 63• lOS. 127 It has been suggested that this medullary recycling may facilitate the excretion of potassium by allowing interstitial K+ concentration to reach 35 to 40 mM. The result will be diminished reabsorption of potassium from the collecting duct as fluid high in potassium content from the distal tubular cortical segments courses through the medulla. 139 Although potassium secretion along the descending limb may contribute to net potassium secretion, the major potassium secreting segments are the late distal tubule (connecting tubule and the initial collecting tubule) and the cortical collecting duct. A variety of factors affect potassium secreting renal cells (Table 2). The principal cell, primarily responsible for potassium secretion, maintains a high intracellular potassium and low intracellular sodium content by active transport along the basolateral membrane (Na+ + K+) ATPase. Basolateral potassium conductance helps maintain a cell electrical negativity. The active transport of potassium is stimulated by several factors including alkalosis, an increase in circulating mineralocorticoids, and an increase in plasma potassium concentration. As summarized recently, 49. 139 there are two properties of the luminal membrane of these cells of particular importance for potassium secretion. One is its high permeability to potasTable 2. Renal Regulation of Potassium Homeostasis-Factors lrifluencing Potassium Secretion in Distal Tubule

Urine Flow rate Plasma [K+] Luminal [K+] Dietary K+ intake Delivery of Na+ Delivery of Cl-

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Acting on distal tubule e.g., Na channel blocker amiloride, triamterene Aldosterone antagonist spironolactone t transtubular potential Beta 2 adrenergic stimulation (epinephrine) Metabolic acidosis

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

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sium, allowing potassium to diffuse along its chemical gradient from cell to lumen. The other is its high permeability to sodium, allowing sodium to diffuse down a chemical gradient from lumen to cell. The diffusion of sodium into the cell offsets to some extent the electrical effect of outward diffusion of potassium and reduces the intracellular negative electrical potential across the apical membrane relative to the basolateral membrane. The result is a lumen negative trans epithelial potential that electrically favors movement of potassium into the lumen. The permeability of the apical membrane to potassium is increased by mineralocorticoids and decreased when tubule fluid is acidified or when the luminal membrane is exposed to barium. Alterations in luminal membrane sodium permeability or trans epithelial voltage will also alter the movement of potassium across this membrane. For example, if the lumen negative transtubular voltage is reduced (less negative), potassium secretion into the lumen decreases. Amiloride reduces the permeability of the apical membrane to sodium. As a consequence of decreased sodium entry, the cell luminal membrane becomes hyperpolarized (more negative) and the luminal transtubular potential decreases. The result is a reduction in potassium secretion. Potassium may also be reabsorped in more distal segments such as the medullary collecting duct in states of K+ depletion. 39 This reabsorption is probably driven by the high K+ concentration in the lumen resulting from distal K+ secretion and continued water reabsorption allowing for K+ diffusion into the interstitium of the papillae and Henle's loop. In states of K+ depletion, net distal nephron reabsorption rather than excretion may occur. 123 Morphological Considerations The potassium secreting tubule segments contain two types of cells. Principal cells, the most numerous in the cortical collecting duct, secrete potassium and are affected by several factors regulating potassium secretion. The less frequent intercalated cells are thought to be primarily responsible for hydrogen secretion and perhaps potassium reabsorption. 126 Interesting morphological changes are associated with alterations in potassium secretion (Figure 7). For example, chronic potassium loading, 124 treatment with aldosterone 122 and reduction of renal mass 140 all induce an increase in the surface area of the basolateral membrane of principal cells in the collecting tubule. These maneuvers induce relative increases in (Na+ + K+) ATPase activity and are all associated with increased excretion of potassium. Similar morphologic changes do not occur in intercalated cell basolateral membranes. 122• 124 These findings are consistent with the view that the sodium pump and basolateral surface area are important in the movement of potassium from interstitium through the cell to the lumen and that principal cells playa major role in potassium excretion.

HYPOKALEMIA Hypokalemia is usually defined as a serum potassium less than 3.5 mEq per 1. General Causes Decreased body potassium can generally be traced to either a decreased intake or an excessive loss in the urine, stool, or sweat. Hypokalemia

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BoIaI Aldosterone

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Figure 7. Schematic representation of effects of adrenalectomy and of aldosterone treatment (7 to 10 days) on basolateral membrane area of principal cells in rat kidney. Cells on left are principal cells and cells on right are intercalated cells. (From Stanton BA: Role of adrenal hormones in regulating distal nephron structure and ion transport. Fed Proc 44:2717-2722, 1985; with permission.)

without body K+ loss can occur by movement of K+ from extra- to intracellular fluid (Table 3). Decreased Intake In response to a decrease in potassium intake, the kidney can reduce potassium excretion to less than 20 mEq per 1 within 4 to 7 days and to 5 to 10 mEq per 1 in 7 to 10 days. 121. 137 Patients must drastically reduce potassium intake to develop hypokalemia. Meats, fruits, and vegetables generally contain enough potassium that dietary depletion becomes unlikely. However, moderately decreased potassium intake in the face of other losses such as with diuretic therapy may lead to hypokalemia. The prolonged ingestion of certain types of clay, particularly in the southeastern United States, is associated with decreased serum potassium probably caused by the binding of potassium in the intestinal tract to the clay. 53 Increased cellular uptake of potassium without actual potassium deficiency may occur in a variety of settings. Alkalosis. On the average, the plasma potassium will drop between 0.2 and 0.4 mEq per 1 per 0.1 unit increase in pH, a relatively mild change. 1 What makes the hypokalemia often more profound in states of alkalosis is the concomitant presence of vomiting, volume depletion, hyperaldosteronism, or use of diuretics. Infusion of bicarbonate may also induce a decrease in serum potassium even if PC02 is kept to a level that precludes a change in pH.44 Thus, bicarbonate ion and not pH may mediate this effect. Hyperinsulinism may induce hypokalemia by promoting the cellular entry of potassium. Clinically, this is most important in the diabetic with

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Table 3. Causes of Hypokalemia DECREASE INTAKE

INCREASED K+ LOSS FROM KIDNEYS

1. Inadequate K+ in diet or IV fluid 2. Ingestion of K+ binding clay-binds dietary

1. Drugs a. Diuretics b. Antibiotics: Amphotericin, carbenicillin, gentamycin, clindamycin, rifampin, outdated tetracycline, polymyxin B, ampicillin, penicillin c. Corticosteroids d. L dopa e. Cis-platin 2. Polyuria 3. Osmotic diuresis-glucose, mannitol, nonreabsorbed anions 4. Hypercalcemia 5. Hypomagnesemia 6. Acid base disorders a. Metabolic alkalosis with bicarbonate loss (early in course of vomiting) b. Metabolic acidosis with bicarbonate loss c. RTA type I-deficient H+ secretion d. RTA type 2-bicarbonate wasting 5. Organic anions---e.g., diabetic ketoacidosis 7. Renal salt wasting with primary renal diseases a. RTA b. Fanconi syndrome-cystinosis, Lowe's, nephronophthisis c. Pyelonephritis d. Obstructive uropathy e. Acute leukemia

KINCREASED INTRACELLULAR K+ UITAKE

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Alkalosis Hyperinsulinism Increased beta adrenergic agonist activity Pseudohypokalemia Early in course of treatment of megaloblastic anemia Transfusion with frozen washed RBC Intravenous hyperalimentation Periodic hypokalemic paralysis Hypothermia Barium chloride ingestion

INCREASED GASTROINTESnl'>AL K+ LOSS

1. Vomiting-may be surreptitious or selfinduced 2. Diarrhea, laxative abuse, cholera 3. Intestinal fistula, tube drainage 4. Ureterosigmoidostomy 5. Villous adenoma of colon-adults 6. Overuse of K+ binding resins INCREASED LOSS THROUGH EXCESSIVE SWEATING OVERZEALOUS DIALYSIS AGAINST A LOW K+ BATH

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8.' -Excessive primary mineralocorticoid activity with low plasma renin . a. Primary hyperaldosteronism b. Adrenogenital syndrome-hypertensive forms, e.g., 17 alpha, 11 beta, hydroxylase deficiency c. Cushing syndrome 9. Excessive secondary mineralocorticoid activity with high renin a. Malignant hypertension b. Renal artery stenosis c. Renin producing tumor d. Necrotizing vasculitis 10. Bartter's syndrome 11. States of pseudohyperaldosteronism (absence of mineralocorticoid excess, aldosterone deficiency) a. Liddle's syndrome b. Licorice abuse c. Carbenoxolone d. Fludrocortisone

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marked hyperglycemia undergoing treatment. Such patients are potassium depleted, but the serum potassium is normal or high probably because the insulin deficiency, acidosis, and high osmolality secondary to hyperglycemia promote cellular potassium movement to the extracellular fluid. Insulin by correcting this redistribution of potassium may unmask the potassium depletion. 74 Persistent hypersecretion of insulin (an insulin pump or intravenous hyperalimentation) may also induce hypokalemia especially if hypoglycemia stimulates epinephrine release. Catecholamines mediate the lowering of plasma potassium primarily by their beta 2 adrenergic agonist activity.34 Hypoglycemia or stress may cause the release of epinephrine sufficient to induce this effect,23, 96 as may the use of salbutamol, a beta 2 agonist,93 used to treat bronchospasm. Pseudohypokalemia may occur with a high white blood cell count, for example in acute myeloid leukemia. 89 Three hours (at room temperature) may elapse before serum electrolytes are measured on a blood sample. During this time, metabolically active leukemic cells may accumulate potassium and cause factitious hypokalemia. This phenomenon will not be present if the plasma potassium is measured immediately. Since pseudohypokalemia will not occur in normal cells concentrated to the same degree as leukemic cells or in leukemic cells if they are incubated at 4° C to decrease pump activity, the hypokalemia is related more to the pump activity than to the number of white blood cells or their concentration. Rapid cell turnover may lead to hypokalemia. For example, hypokalemia may develop from the transfer of serum K+ to rapidly produced red cells and platelets early in the treatment of megaloblastic anemia. This generally occurs within 48 hours of starting folic acid or vitamin B12 therapy and may lead to marked drop in potassium. 76 Other anemias are less likely to induce such hypokalemia since cell turnover during treatment is not as rapid. Transfusion of frozen, deglycerolyzed, washed red blood cells which become K+ depleted may also lead to hypokalemia within 4 hours as the depleted cells avidly take up K+ from the patient's serum. 98 Hypokalemia may also occur in patients receiving intravenous hyperalimentation l33 who have been in marked negative nitrogen balance. Such hypokalemia is related in part to hyperinsulinism and may be augmented as the catabolic state is reversed and new cells accrue during the increased caloric intake. We have seen serum potassium values drop to less than 2 mEq per I in this setting. Hypothermia for 24 to 48 hours may cause a significant decrease in serum potassium to approximately 2.5 mEq per I, an effect that is reversible within 6 to 12 hours upon rewarming.72 In fact, hyperkalemia may develop to levels of 7.0 to 7.5 mEq per I if potassium therapy is given during this time. Replacing only potassium lost from urine and gastric secretions without supplemental K+ will not cause hyperkalemia. Barium ingestion may cause life-threatening hypokalemia by trapping potassium within the cells. 78, 131 In this situation, the continued activity of the pump allows potassium to accumulate in the cells, but the K+ channels that permit passive egress of potassium are blocked, This effect may significantly impair the normal cell volume regulatory response of tissue

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

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1.7 1.6

663

HYPOTONIC MEDUII

J

1.5

S

;

1.4 1.3 1.2

1.1

"CONTOOL N.6

1.0

o

2

4

6

8

10 12 14 16 18 20 22 24 26 28 30

MNUTES

Figure 8. Effect of different concentrations of barium on cell volume regulation of isolated, collapsed proximal straight tubules in hypotonic medium. All groups of tubules maintained a relatively constant volume in isotonic medium. Barium treated tubules were incubated for 20 minutes in 10-3 or 10-2 M BaCl2 prior to exposure to hypotonic medium at time O. Data expressed as mean ± SE and are computed by dividing experimental volume by control volume, defined as steady state volume just prior to immersion in hypotonic medium. (From Welling PA, Linshaw MA, Sullivan LP: Effect of barium on cell volume regulation in rabbit proximal tubules. Am J Physiol 249:F20-F27, 1985; with permission.)

exposed to hypotonic medium. 135 This provides evidence of the role of K+ in the regulation of cell volume (Figure 8). Periodic paralysis, an autosomal dominant illness with variable penetrance and clinical expressivity in females, particularly in the hypokalemic form, is characterized by a sense of "aura" of onset of paralysis with attacks brought on by rest after heavy exercise, exposure to cold, or anxiety. Attacks may also occur following a heavy meal, particularly one high in carbohydrates. 143 Attacks of weakness or paralysis may last 6 to 24 hours. Both begin in the extremities and involve major muscle groups sufficient to cause quadriplegia. The disease may also affect respiratory muscles. The attacks are more likely to occur during the night. During attacks, the urine potassium excretion actually decreases, and potassium is taken up primarily by skeletal muscle. The cause of the paralysis does not appear to relate to abnormalities of nerve conduction or myoneural transmission but seems to be intrinsic to the muscle. Acute episodes are treated with KCl given orally. Chronic administration of oral potassium, K+ sparing diuretics, or a low carbohydrate diet may help prevent other attacks. 77 , 128 An acquired form of hypokalemic periodic paralysis common in oriental males is associated with hyperthyroidism and increases sensitivity to catecholamines. 81 Beta adrenergic blockers or careful control of the hyperthyroidism will usually alleviate these attacks. Excessive gastrointestinal fluid losses are usually an obvious cause of hypokalemia. Several liters of gastric, intestinal, and pancreatic secretions enter the intestinal lumen daily. If these fluids are insufficiently reabsorbed or if hypersecretion occurs, significant potassium depletion can occur. Since gastric fluid is relatively low in K+ content, approximately 10 mEq per 1,40

664

MICHAEL

A.

LINSHA W

K loss from this source is relatively minor. The ensuing alkalosis from loss of acid and the resulting renal K+ loss is a more important cause of the hypokalemia. 65 If volume depletion accompanies the intestinal fluid losses, hyperaldosteronism can contribute to hypokalemia by increasing the renal excretion of potassium. It should be remembered that vomiting, particularly self-induced, or diarrhea associated with excessive intake of laxatives may be surreptitious and difficult to identify historically. Potassium losses may be substantial in cholera. 134 Patients with islet cell tumors or hyperplasia of non beta cell origin may develop severe watery diarrhea (the pancreatic cholera syndrome) and hypokalemia. 132 The diarrhea may be related to increased secretion of vasoactive intestinal peptide that increases fluid secretion in Brunner's glands 68 located in the duodenal submucosa. Increased loss through excessive sweating. The sweat contains small amounts of potassium-approximately 9 mEq per 1. 100a Losses through this route are normally negligible. However, during heavy exercise, particularly in hot weather, profuse sweating may cause substantial loss of potassium. 70 The potassium depletion may induce vasoconstriction with decreased muscle perfusion ultimately increasing the risk for ischemia and rhabdomy0lysis. 71 Moreover, volume depletion and exercise induced release of catecholamines may lead to aldosterone hypersecretion and renal potassium loss. Overzealous dialysis against a dialysate low in potassium may induce total body potassium depletion and hypokalemia even in the presence of chronic renal failure. 107 Hypokalemia in this setting may be profound if there are superimposed gastrointestinal losses, poor intake, or if a patient is sick enough to require concomitant intravenous hyperalimentation. The rapid correction of acidosis during hemodialysis may also induce hypokalemia by inducing the cellular uptake of extracellular potassium. Increased potassium loss through the kidneys (Table 2) Potassium secretion, as reviewed in detail by Wright and Giebisch,139 will increase when the peritubular potassium concentration increases or when the luminal potassium concentration decreases. An increase in flow rate through the distal nephron will also increase potassium secretion probably by minimizing the effect that potassium diffusion into the lumen will have on raising potassium concentration in luminal fluid during low flow rates. Potassium secretion is also sensitive to sodium and chloride content in luminal fluid. Potassium secretion is stimulated when luminal chloride concentration is decreased and when luminal sodium concentration is increased. Volume expansion will increase potassium secretion primarily by increasing urine flow rate. Other factors that increase potassium secretion include aldosterone, an increase in the plasma bicarbonate concentration, and an increase in circulating levels of ADH. These factors may exert their effect by increasing the luminal membrane permeability to potassium. Therefore, renal losses usually relate to one or more of the above factors stimulating distal potassium secretion. Specific Causes of Renal Hypokalemia (Table 3) Diuretics. Agents that decrease salt and fluid reabsorption in the proximal tubule (mannitol or carbonic anhydrase inhibitors), loop of Henle

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

665

(furosemide), or diluting segment (thiazide) may increase flow to the distal nephron and drive potassium secretion. Acetazolamide increases distal delivery of bicarbonate that acts as a relatively nonreabsorbable anion and further drives potassium secretion. Furosemide inhibits salt reabsorption in the loop of Henle, interfering with the cotransport of N a +, Cl-, and K+ at this site. With sufficient volume depletion, diuretics may induce hyperaldosteronism. 129 Other drugs. The distal delivery of relatively nonreabsorbable anions such as bicarbonate l16 (renal tubular acidosis) and carbenicillin 124a are all potential causes of hypokalemia. Tubulotoxic antibiotics such as gentamycin54 may cause renal potassium loss. Corticosteroids may induce hypokalemia if mineralocorticoid activity is potent enough. Drug induced hypokalemia has recently been reviewed. 21 Hypomagnesemia. Magnesium depletion may cause renal potassium wasting. 119 Cis-platin probably by virtue of its magnesium wasting effect leading to hypomagnesemia has been associated with hypokalemia and potassium wasting. 16a The potassium wasting and hypokalemia resolve when hypomagnesemia is treated with supplemental magnesium salt. The mechanism for potassium wasting in states of hypomagnesemia has not been defined. However, it has been suggested that since the major site of potassium reabsorption occurs in the ascending loop of Henle, and reabsorption of potassium in this site is ultimately driven by the activity of a magnesium dependent (Na+ + K+) ATPase, cellular depletion of magnesium in these cells may contribute to renal potassium wasting. Since there is experimental evidence that magnesium depletion increases plasma aldosterone and the aldosterone antagonist spironolactone ameliorates potassium wasting in patients with magnesium wasting, magnesium loss may in some way cause hyperaldosteronism with subsequent renal potassium wasting. 115 Polyuria may be associated with hypokalemia if urine volume is sufficiently large. 106 Even though urine potassium concentration may be reduced to 5 to 10 mEq per 1, if urine volume is sufficiently high (e.g., 8 to 10 1 per day) potassium excretion may exceed potassium intake with resulting hypokalemia. Hypercalcemia particularly in patients with malignancies may be associated with hypokalemia secondary to renal potassium wasting. 2 The mechanism is not known. Hypermineralocorticoidism. The other major cause of renal potassium wasting relates to increased mineralocortocoid activity, either primary hyperqldosteronism with suppressed plasma renin activity, secondary hyperaldosteronism with elevated plasma renin activity, or states of pseudohyperaldosteronism in which mineralocorticoid excess from a nonaldosterone agent is present. Mineralocorticoids stimulate Na reabsorption and K+ and H+ secretion along the distal nephron, particularly in the face of sufficient distal delivery of Na and water. Primary hyperaldosteronism is associated with hypertension, metabolic alkalosis, hypokalemia, polyuria, weakness, tetany, and increased serum aldosterone and decreased plasma renin activity. There also may be mild hypernatremia. 28 Patients may be asymptomatic with normal serum K+ if volume expansion is not present. Volume expansion accounts for the hypertension, hypernatremia, and hypokalemia. 12, 101, 117 In normal subjects,

666

MICHAEL

A. LINSHA W

a salt load still decrease aldosterone and renin by volume expansion and potassium wasting will not occur. In patients with hyperaldosteronism, a salt load will not suppress aldosterone, and the augmented distal flow will enhance potassium secretion. 15. 66. 138 Thus, sodium chloride loading may unmask hyperaldosteronism and generate hypokalemia in a previously normokalemic patient. If distal flow rate is decreased from volume depletion, potassium secretion may not increase even though aldosterone levels are elevated. 117 Cushing's syndrome. This illness remains primarily a clinical diagnosis and is associated with truncal obesity, muscle wasting, hirsutism, hypertension, metabolic alkalosis, and hypokalemia. Renin activity may be normal to high particularly11. 31 in benign adrenal hyperplasia. Since cortisol has relatively small mineralocorticoid activity, the hypertension and hypokalemic alkalosis are not usually severe. However, if hypertension and hypokalemia are severe, one should suspect the presence of another more potent mineralocorticoid, such as deoxycorticosterone or aldosterone, that occasionally may be elevated in patients with Cushing's syndrome and may suppress plasma renin activity. 16, 61 Licorice contains glycyrrhizinic acid, a steroid similar to deoxycorticosterone. If taken in excess, a hypermineralocorticoid state may develop even though plasma aldosterone levels are suppressed. 17, 30 Licorice may be ingested through candy, chewing tobacco or alcohol. Carbenoxolone. This is an agent used in treating peptic ulcer disease and is another mineralocorticoid-like substance that may induce hypokalemia. 5 Fludrocortisone exerts a similar effect. 83 Congenital adrenal hyperplasia. There are two forms of congenital adrenal hyperplasia associated with hypokalemia. 13. 20, 91, 115 Eleven beta hydroxylase deficiency is associated with defective cortisol synthesis and leads to increased ACTH production. Deoxycorticosterone, an active mineralocorticoid, also increases as do adrenal androgens whose synthesis remains unimpaired. In addition to hypertension and hypokalemia, such patients may become virilized. In these patients, the conversion of deoxycorticosterone to corticosterone is impaired. Seventeen alpha-hydroxylase deficiency also is associated with defective cortisol synthesis leading to increased ACTH production. Deoxycorticosterone production increases; but since the conversion of deoxycorticosterone to corticosterone is unimpaired, both of these mineralocorticoids can contribute to the hypermineralocorticoid state. Synthesis of adrenal and gonadal androgens and estrogens is impaired in this entity and normal sexual maturation is inhibited. Females may not develop secondary sexual characteristics and males may become pseudohermaphrodites. Bartter's syndrome. This rare disorder is characterized by growth failure, muscle weakness, cramps, poor feeding, vomiting, polyuria, constipation, and normal blood pressure. Patients typically have hypokalemic metabolic alkalosis with renal potassium wasting, hyperaldosteronism, and hyperreninemia. Renal biopsy shows hyperplasia of the juxtaglomerular apparatus. 7 There is a decreased response to pressor agents that may reflect a general decrease in peripheral vascular resistance occurring with prolonged potassium depletion. However, the basic defect in Bartter's syndrome is not vascular insensitivity to pressor agents, since vascular respon-

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

667

siveness to such agents can be restored by volume expansion. 56. 136 Several other entities associated with chloride depletion and/or increased potassium loss through the gastrointestinal tract or kidney may present a similar picture and include: surreptitious vomiting, laxative abuse or diuretic use, chloride losing diarrhea, chloride depletion from defective infant formula, renal disease causing potassium loss such as cystinosis, magnesium losing tubulopathy, and calcium losing tubulopathy. Gastrointestinal losses are usually associated with low sodium chloride content in the urine in contrast to Bartter's and related syndromes where chloride loss is characteristic. Chronic primary renal diseases causing potassium loss should be easily diagnosed and diuretic abuse, unlikely in children, can be diagnosed with a urine screen for diuretics. Two other metabolic potassium losing disorders, magnesium or calcium losing tubulopathies, are similar to Bartter's syndrome but may be differentiated on several points recently reviewed by Gill50 (Table 4). These entities are characterized by hypokalemic alkalosis, hyperreninemia and hyperaldosteronism. Consequences of Hypokalemia Symptoms and signs from hypokalemia are unlikely unless the serum K+ drops below 2.5 to 3 mEq per 1 (Table 5). Neuromuscular. Nonspecific findings include lethargy, confusion and tetany. Autonomic dysfunction may lead to orthostatic hypotension. 14 Hypokalemia can worsen hepatic encephalopathy6 since hypokalemia increases the production of ammonia in the renal cortex and in addition, metabolic alkalosis accompanying hypokalemia may increase the ratio of ammonia to ammonium ion (NH3:NH4 +) and allow tissue and cerebrospinal fluid NH3 content to increase. Hypokalemia may affect skeletal, smooth, and cardiac muscle. Symptoms range from mild weakness to paralysis, quadraplegia, and respiratory insufficiency. Muscle weakness does not usually occur until plasma potassium is less than 2.5 mEq per l. Generally, the lower extremities are first involved, particularly the quadriceps muscles. The weakness tends to ascend, ultimately involving the respiratory muscles. The muscles may become tender and cramps are not uncommon. 41 Rhabdomyolysis and myoglobinuria with renal failure can occur in patients with severe potassium depletion 69 particularly with serum values less than 2.5 mEq per l. Intestinal ileus 106 as well as ureteral dilatation and functional obstructive uropathy4B have occurred with hypokalemia. The cardiac effects are serious and include myocardial cell necrosis and arrhythmias such as premature atrial or ventricular beats, bradycardia, atrioventricular block, and possibly ventricular tachycardia or fibrillation. Patients taking digitalis preparations are more sensitive to digitalis-induced arrhythmias in the presence of hypokalemia. llB The specific electrocardiographic changes include depression of the ST segment, a flattened T wave, increased prominence of the U wave and prolongation of the QU interval. 130 These are all indicative of aberrations in ventricular repolarization. Eventually the P wave becomes more prominent and the PR interval may become prolonged with widening of the QRS complex (Figure 9). Vascular. Exercise increases muscle perfusion to meet excess metabolic demands. The vasodilation mediating the increased perfusion is stimulated

r~ ~

~

Table 4. Potassium Losing Tubulopathies: Differential Features

Clinical Laboratory Serum Urine

Renal histology

BARTIER'S SYNDROME

MAGNESIUM-LOSING TUBULOPATHY

CALCIUM-LOSING TUBULOPATHY

growth blood pressure other

delayed normal tetany

normal normal tetany

delayed normal polyuria, polydipsia

potassium magnesium calcium potassium magnesium calcium concentrating ability diluting ability

~

~ ~ ~

~ normal normal

~

or normal normal

t t

\

~ ~ ~ juxtaglomerular apparatus hyperplasia

t t

~ normal normal normal

t

normal

t

~ normal may have juxtaglomerular apparatus, hyperplasia, nephrocalcinosis

t

= increased ~ = decreased

From Gill JR, Jr: Potassium in cardiovascular and renal medicine. In Kidney Disease, Vol 6. Marcel Dekker, 1986, pp 121-131, with permission.

~

o == ~

t"'

;>

t:'

z

[Jl

~

669

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

Table 5. Clinical and Physiological Consequences of Hypokalemia NEUROMUSCULAR-DECREASE IN EXCITABILITY

1. Muscular a. Skeletal weakness, paralysis b. Smooth-intestinal ileus, ureteral dilatation c. Cardiac---myocardial cell necrosis, arrhythmia, and EKG changes d. Rhabdomyolysis-myoglobinuria 2. Neurological a. General-lethargy, confusion, tetany b. Autonomic insufficiency--orthostatic hypotension c. Hepatic encephalopathy

II 'I

VASCULAR

Acute HyPokalemia-Vasoconstriction; Chronic Hypokalemia-Vasodilatation METABOLIC

1. Hyperglycemic and carbohydrate intolerance 2. Negative nitrogen balance 3. Decreased secretion of aldosterone, insulin RENAL

1. 2. 3. 4. 5. 6.

Decreased concentrating capacity-polyuria, polydipsia Nephropathy-decreased GFR and RBF Increased renal ammonia production-hepatic coma Increased bicarbonate reabsorption-maintenance of metabolic alkalosis Sodium retention--edema Decreased chloride reabsorption-alkalosis

by release of potassium from skeletal muscle. This response is impaired in hypokalemia, perhaps contributing to cramps, ischemia, and eventual rhabdomyolysis. 70 The potassium-induced vasodilation is probably related to stimulation of (Na+ = K+) ATPase activity in the smooth muscle cells resulting in hyperpolarization of the membrane. Whereas acute decreases in potassium are associated with increased peripheral vascular resistance (vasoconstriction), chronic potassium deficiency is associated with decreased vascular resistance, vasodilation, and decreased blood pressure. 94 Metabolic. Hypokalemia, by suppressing insulin secretion, may lead to carbohydrate intolerance and hyperglycemia. 57 Glycogen synthesis is impaired in hypokalemia46 and patients may have an abnormal glucose tolerance test that reverses upon restoring K+ balance. 29 Aldosterone secretion may also be suppressed24,64 and may help minimize urinary K+ excretion. Negative nitrogen balance can occur in K+ deficiency since K+ is needed for protein synthesis. 80 Potassium is required to restore positive nitrogen balance during intravenous hyperalimentation. no, 133 Potassium

Plasma K+. meq/L

4.0

3.0

2.0

1.0

Figure 9. Electrocardiographic changes in relation to plasma potassium in mEq per liter. (From Surawicz B: Relationship between electrocardiogram and electrolytes. Am Heart J 73:814-834, 1967; and adapted from Rose BD: Clinical physiology of acid-base and electrolyte disorders, 2 ed. McGraw-Hill, 1984, pp 248-268, 567-578, 579-616; with permission.)

670

MICHAEL

A. LINSHAW

deficiency may cause growth failure in animals 62 , 73 and may contribute to growth failure in children with Bartter's syndrome. Renal effects. A nephropathy associated with interstitial fibrosis and tubular atrophy may occur. Potassium depletion leads to vacuolar lesions in the proximal and sometimes distal tubules. The abnormalities usually take at least a month of chronic hypokalemia to develop and are reversible with potassium repletion unless significant fibrosis or loss of renal tissue has occurred. 99, 113 A relatively mild concentrating defect occurs with chronic but not acute hypokalemia and diluting ability seems to be unaffected. 109 Hypokalemia may lead to sodium retention and edema that may worsen with potassium replacement, perhaps reflecting the movement of intracellular sodium to the extracellular space as potassium re-enters the intracellular compartment. IB , 42, 112, 137 While cardiac, neuromuscular, and some renal effects of potassium loss are detrimental to the organism, other effects such as the suppression of insulin and aldosterone, the increased reabsorption of potassium, and the increase in renal ammonium production and excretion (that may spare potassium) may protect the organism against hypokalemia by decreasing the cellular uptake and increasing the urinary conservation of potassium. Diagnostic Evaluation (Table 6) A careful history will often reveal the cause of hypokalemia. Questions should relate to poor intake, starvation, anorexia, or clay ingestion as well as the use of diuretics, antibiotics, steroids, or other drugs that may induce hypokalemia. Excessive sweating with exercise in hot weather and intestinal losses as with vomiting, diarrhea, and gastrointestinal tube drainage also should become obvious when obtaining the history. A search should be made for periodic episodes of muscle weakness or paralysis, excessive intake of licorice, constipation, polyuria, polydipsia, growth failure, nocturia, paresthesias and cramps, weight loss, and evidence of malignancy (e.g., lung, pancreatic, or ovarian tumors that might produce ACTH). Physical findings of diagnostic aid include the presence of hypertension, growth failure, tetany, volume depletion, dehydration or volume overload with edema, abdominal or flank bruits, abdominal or pelvic masses and signs of Cushing's disease such as truncal obesity, striae, muscle wasting, and hirsutism. The presence of virilization or impaired secondary sexual development or pseudohermaphroditism may provide a clue to adrenal hyperplasia. If the history and physical examination do not reveal the diagnosis, a logical approach can be summarized as follows (Table 7).45,106 Urinary potassium conservation occurs within 4 or 5 days, is highly efficient within a week to 10 days, and urine K+ concentration can be Table 6. General Diagnostic Approach to Hypokalemia HISTORY AND PHYSICAL EXAMINATION URINARY K+ EXCRETION ACID BASE STATUS-ACIDOSIS, ALKALOSIS EXTRACELLULAR FLUID VOLUME STATUS-URINARY Na+ AND Cl- EXCRETION PRESEJ>.:CE OR ABSENCE OF HYPERTENSION

"t:I

Table 7. General Approach to Hypokalemia*

~

Hypo~alemia

I

en

I

True Hypokalemia 1

Pseudohypokalemia---check WBC,-run serum K+ immediately

::t:

Blood Pressure Normal ~

Blood Pressure Elevated

. - - - - - - - - -I- - - - - - - - - 1

Urine K+>20 mEqlliter renal K+ loss or problem is acute «4-7 days) Check blood pH

Urine K+<20 mEq/liter non-renal K+ loss, e.g. gastrointestinal, sweating, low intake or problem chronic (>7-10 days)

Urine K+>30 mEq/day suggests renal loss of K+ Check plasma renin activity

Acid

Alkaline

Renin activity high or normal

RTA-Type 1, 2 Diabetic ketoacidosis Renal insufficiency Salt wasting Fanconic syndromes, e. g. cystinosis

Vomiting with increased urine Na and HC03 and decreased ClDrugs e.g. diuretics, carbenicillin Excessive mineralocorticoid as with Bartter's syndrome, magnesium and calcium losing nephropathies

Diuretic use Renal artery stenosis Malignant hypertension Renin-producing tumor Cushing's syndrome Primary nephropathy (e.g., salt wasting, obstruction)

Check serum aldosterone

Aldosterone-High

Aldosterone-Low (suppressed) Exogenous-nonaldosterone mineralocorticoid Licorice Fludrocortisone Carbenoxolone Liddle's syndrome Cushing's syndrome Adrenogenital

1

Acid Diarrhea or other nongastric loss of intestinal fluid Ureterosigmoidostomy

I

I

i

Check Blood pH

Check adrenal vein Aldosterone, epinephrine, cortisol

I

Alkaline Vomiting with new steady state and low urinary Na, Cl, HC03 Cloride loss (e.g., familial chloride diarrhea or chloride-deficient infant formula)

C a::

I

I

Aldosterone high on one side-tumor Aldosterone-drops in upright position

Aldosterone high on two sideshyperplasia

Urine K+<30 mEq/day suggests gastrointestinal loss or previous diuretic or other drug therapy which has been discontinued i Renin activity low

a a:: t"l a

~

f:!l

en

~

I:l

::t: -< C3

~

a::

;;;:

Aldosterone-rises in upright position

"Approach to diagnostic evaluation of hypokalemia. (Adapted from Rose BD: Clinical physiology of acid-base and electrolyte disorders, 2 ed. McGraw-Hill, 1984, pp 248-268, 567-578, 57~16; and Gabow PA, Peterson LN: Renal and electrolyte disorders, 2 ed. Schrier RW (ed). Little, Brown, 1980, pp 183-221.)

Ol

--t

.....

672

MICHAEL

A.

LINSHA W

decreased to 5 mEq per l,l21, 137 Urine potassium should be less than 20 mEq per 1 unless there is renal potassium wasting. It must be remembered that potassim wasting from excessive diuretic use may have occurred over a period of time, and yet urinary potassium excretion may be low if the patient has been off diuretics for several days. If potassium depletion is severe enough, the urine potassium may be low even with continued diuretic use. Generally, however, a low urine potassium indicates that the potassium loss is either intestinal or elsewhere (excessive sweating or burns) or the problem is chronic and that renal adaptive potassium-conserving mechanisms are active. 45, 106 If the urine potassium is more than 20 mEq per 1, one should look for renal potassium wasting. However, if the problem is acute (a few days), renal adaptive mechanisms that conserve potassium may not be dperating sufficiently. Moreover, renal potassium wastil)g may occur in states of metabolic alkalosis without primary renal disease e. g., as a result of vomiting,65 chloride losing diarrhea lO or chloride depletion from chloride deficient formula 79 if the elevation in serum bicarbonate level and the degree of hyperaldosteronism are sufficient to induce renal potassium loss. The acid base state may be helpful in the diagnosis as suggested in Table 7. The state of the extracellular volume is important since volume depletion with weak pulses, a decrease in skin turgor, and hypotension may be seen in vomiting, diarrhea, or other gastrointestinal loss of fluid or the overuse of diuretics. Volume overload with hypertension occurs with mineralocorticoid excess. The urine chloride may help in this regard since it should be low in the presence of volume depletion (e. g., vomiting, chloride-losing diarrhea, chloride deficient formula, or discontinued diuretic therapy). An elevated urine chloride suggests continued diuretic use, surreptitious use of drugs, Bartter's syndrome (or related tubulopathies), or hypermineralocorticoidism. If the blood pressure is elevated, the diagnostic approach outlined in Table 7 should help direct the physician to the appropriate diagnosis. Treatment of Hypokalemia As a rough approximation, in adults a drop in serum potassium from 4 to 3 mEq per liter is associated with a potassium deficit of 100 to 400 mEq. The serum potassium will drop to 2 mEq per liter with an additional 200 to 400 mEq loss, but thereafter hypokalemia tends not to worsen since the cells release potassium and maintain plasma potassium at about this level. 114, 125 It must be remembered that potassium depletion may occur without hypokalemia, and hypokalemia may occur without total body potassium depletion. The relationship between serum potassium and total body potassium content has no definite correlation, and thus there is no readily available method to determine total body potassium loss. Because changes in plasma potassium concentration may have significant effects on neuromuscular and cardiac irritability, large acute loads of potassium may be poorly tolerated even with severe intracellular potassium depletion. Therefore, it is generally wise to repair potassium deficits slowly. If potassium deficits must be repaired quickly because of severe muscle weakness or paralysis or intoxication with digitalis, serum potassium concentrations should be watched carefully and electrocardiographic monitoring

673

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

should be initiated to document the effects of changing serum potassium levels. The initial aim of therapy is to eliminate danger from hypokalemia and avoid danger from hyperkalemia. The remainder of the potassium deficit should occur over days rather than hours. Treating acidosis may worsen hypokalemia as acidosis may mask to some extent the severity of potassium depletion. Whenever possible, the potassium deficit should be replaced by the oral rather than intravenous route. This approach minimizes the risk of hyperkalemia. Several preparations of potassium are available for both oral and intravenous use including potassium chloride, bicarbonate, phosphate, gluconate, citrate, and acetate (Table 8). Since chloride deficiency often is associated with hypokalemia and potassium loss is augmented by chloride depletion, potassium deficits are best repaired by providing chloride ion particularly in the presence of metabolic alkalosis. 106 Potassium chloride solutions are safe and readily absorbed though unpleasant. Epigastric distress and ulceration of the bowel mucosa are more likely to occur with solid preparations of potassium. Providing these forms of K after meals, when gastric volume is large and gastric motility is active, allows the tablet or capsule to move about and reduce high local concentrations of potassium that might irritate the mucosa. Solid potassium preparations should not be used in patients with disorders of intestinal emptying. 58 Oral solutions of potassium with some of the organic anions are better tolerated and may be appropriate if chloride is provided through another source. In states of acidosis, potassium bicarbonate or citrate is a more appropriate replacement therapy. Potassium can be provided with potassium rich foods such as orange juice or bananas, but chloride intake under these circumstances may be insufficient and the increased caloric intake may be a problem to patients who are obese. The potassium content of several foods is summarized in Table 9. Potassium replacement of 3 mEq per kg per day plus maintenance needs is appropriate to initiate K+ repletion. 136a High concentrations of oral K+, e.g., 70 to 80 mEq per liter may cause pylorospasm and vomiting.

II

Table 8. List of Selected Commercially Available Potassium Preparations TYPE

NAME

COMPANY

CONCENTRATION IN mEq

K

Phosphate Bicarbonate or Citrate Gluconate Chloride

K-phos MF Neutral Original K-Iyte Polycitra Polycitra K Kaon Elixir Kay Ciel RumK Oral solution 10% 20%

Beach Beach Beach Mead Johnson Willen Willen Adria Berlex Fleming Roxane

1.1/tab 1.lItab 3.7/tab 25 (or 50/tab)

Na 2.9/tab 13/tab O/tab 0

!1I,

i '~

11' !;

J.'

g; n~'

1.0lml 2.0/ml 20/15 ml (grape) 20/15 ml 20/10 ml (rum)

1.0lml 0

40/30 ml (coconut) 80/30 ml (grapefruit)

Compiled from Physicians Desk Reference (PDR) 40th ed, Medical Economics, Oradell, NJ,1986.

674

MICHAEL

A.

LINSHAW

Table 9. Potassium Content of Selected Foods POTASSIUM FOOD

Vegetables Asparagus Beans Beets Broccoli Carrots Carrot-raw Celery-raw Corn Peas Tomat~anned

Tomato--raw Potato--boiled

AMOUNT

cup drained cup drained cup drained cup drained cup drained 1 medium 1 stalk V. cup drained V. cup drained Y2 cup drained 1 medium V. cup drained V. V. V. V. V.

FruIts Apple-pared Applesauce-canned Banana Blueberries Grapefruit Orange Peach-pared Pear Pe~anned, syrup Pineapple-canned Strawberries Watermelon slice Dairy Products Eggs, large medium Cream, light Milk, regular skim low sodium Cereal Dried Oatmeal, cooked Bread, Grain, Crackers Regular bread Whole wheat bread Rice, cooked Saltines English muffin Meat, Fish Muscle; red meat Organ meats Chicken white meat dark meat Turkey white meat dark meat Fish-various types

1 medium Y2 cup 1 medium V. cup V. cup 1 medium 1 medium 1 medium V. cup V. cup Y2 cup slice 6" x 2" 1 1 1 tablespoon 1 cup 1 cup 1 cup 1 cup 1 cup 1 slice 1 slice 1 ounce 1 square

(mEq)

4.2 1.6 3.6 5.3 2.4 6.3 3.5 2.0 2.1 6.7 7.7 5.7 4.3 2.4 11.3 1.5 3.0 6.7 6.9 5.5 2.7 3.1 3.1 16.0 1.7 1.5 0.5 9.5 10.4 15.8 most < 1-1.5 3.7

V.

0.66 1.7 1.0 0.09 0.6

1 ounce 1 ounce

1.5-3 2.0

1 ounce 1 ounce

3.0 2.3

1 ounce 1 ounce 1 ounce

3.0 2.9 1.6-3.8 Table continued on opposite page

675

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

Table 9. Potassium Content of Selected Foods Continued POTASSIUM FOOD

AMOUNT

(mEq)

Juices

Apple Apricot nectar Cranberry Grape Grapefruit . Orange-canned fresh . Pear nectar Pineapple Prune Tomato

3% ounces 3V2 ounces 3% ounces 3% ounces 3% ounces 3% ounces 3% ounces 3V2 ounces 3% ounces 3% ounces 3% ounces

2.6 3.9 0.25 3.0 4.1 4.9 5.1 1.0 3.8 6.0 5.8

Adaptedfrom Alpers DH, Clouse, RE, Stenson WF: Manual of Nutritional Therapeutics. Little Brown, Boston, 1983, p 64; and Bloch AS, Shils ME: Modern Nutrition in Health and Disease (appendix). Philadelphia, Lea & Febiger, 1980, pp 1278--1282.

If intravenous potassium is to be used, care must be taken to avoid abrupt rises in serum potassium. In general, potassium should not be administered in states of shock, poor renal function or oliguria, or the presence of hyperkalemia and should be used with care when the patient is acidotic, particularly if clinically unstable and acidosis may worsen. 136a Providing 3 mEq per kg per day plus maintenance over 3 to 4 days should be adequate potassium treatment unless there are large, ongoing renal or nonrenal potassium losses. Potassium may be used in a concentration of 20 to 30 mEq per I without difficulty. The dextrose from the intravenous infusion may induce insulin secretion that could lower plasma potassium concentration somewhat, especially if only 20 mEq per liter are used. 75 The risk of overdosing with potassium can be significantly minimized if the concentration of potassium is limited to 40 mEq per liter. Concentrations above 60 mEq per liter are likely to irritate and perhaps sclerose a peripheral vein. Rarely, in life-threatening situations, higher amounts of potassium must be given. We have observed children who have needed 100 or more mEq per liter of potassium to maintain serum potassium in the face of ongoing carbenicillin therapy. Such situations are uncommon in clinical medicine. Concentrations above 40 mEq per liter should not be used unless careful electrocardiographic monitoring is available.

REFERENCES 1. Adrogue HJ, Madias NE: Changes in plasma potassium concentration during acute acidbase disturbances. Am J Med 71:456-467, 1981 2. Aldinger KA, Samaan NA: Hypokalemia with hypercalcemia: Prevalence and Significance in treatment. Ann Intern Med 87:571-573, 1977 3. Alexander EA, Levinsky NG: An extrarenal mechanism of potassium adaptation. J Clin Invest 47:740-748, 1968 3a. Alpers DH, Clouse RE, Stenson WF: Manual of nutritional therapeutics. Little Brown, ~"ston, 1983, p 64

'I

]1

676

!

MICHAEL

A. LINSHAW

4. Anderson EC, Langham WH: Average potassium concentration of the human body as a function of age. Science 130:713-714, 1959 5. Armanini D, Karbowiak I, Krozowski Z, et al: The mechanism of mineralocorticoid action of carbenoxolone. Endocrinology 111:1683-1686, 1982 6. Artz SA, Paes IC, Faloon WW: Hypokalemia-induced hepatic coma in cirrhosis: Occurrence despite neomycin therapy. Gastroenterology 51:1046-1053, 1966 7. Bartter FC, Pronove P, Gill JR, et al: Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33:811-828, 1962 8. Bia MJ, DeFronzo RA: Extrarenal potassium homeostasis. Am J Physiol240:F257-F268, 1981 . 9. Bia M, Tyler K, DeFronzo R: Regulation of extarenal potassium homeostasis by adrenal hormones in rats. Am J Physiol242:F641-F644, 1982 10. Bieberdorf FA, Gorden P, Fordtran JS: PathogeneSiS of congenital alkalosis with diarrhea. Implications for the physiology of normal ileal electrolyte absorption and secretion. J Clin Invest 51:1958-1968, 1972 11. Biglieri EG: Adrenocortical components in hypertension. Cardiovasc Rev Rep 3(5):734-748, 1982 12. Biglieri EG, Forsham PH: Studies on expanded extracellular fluid and responses to various stimuli in primary aldosteronism. Am J Med 30:564-576, 1961 13. Biglieri EG, Herron MA, Brust N: 17-Hydroxylation deficiency in man. J Clin Invest 45:1946-1954, 1966 14. Biglieri EG, McIlroy MB: Abnormalities of renal function and circulatory reflexes in primary aldosteronism. Circulation 33:78--86, 1966 15. Biglieri EG, Slaton PE, Jr, Kronfeld SJ, et al: Diagnosis of an aldosterone-producing adenoma in primary aldosteronism. An evaluative maneuver. J Am Med Assoc 201:510-514, 1967 16. Biglieri EG, Stockigt JR, Schambelan M: Adrenal mineralocorticoids causing hypertension. Am J Med 52:623-632, 1972 16a. Blachley JD, Hill JB: Renal and electrolyte disturbances associated with cisplatin. Ann Int Med 95:628--632, 1981 17. Blachley JD, Knochel JP: Tobacco chewer's hypokalemia: Licorice revisited. N Engl J Med 302:784-785, 1980 18. Blahd WH, Bassett SH: Potassium deficiency in man. Metabolism 2:218--224, 1953 18a. Bloch AS, Shils ME: Appendix In Goodhard RS, Shils ME (eds): Modern nutrition in health and disease, ed. 6. Lea & Febiger, Philadelphia, 1980, p 1278--1282 19. Bomsztyk K, Wright FS: Effects of transepithelial fluid flux on transepithelial voltage and transport of calcium, sodium, chloride, and potassium by renal proximal tubule. Kidney Int 21:269, 1981 20. Bongiovanni AM, Root, AW: The adrenogenital syndrome. N Engl J Med 268:1283-1298, 1342-1351, 1391-1399, 1963 21. Brass EP, Thompson WL: Drug-induced electrolyte abnormalities. Drugs 24:207-228, 1982 22. Bratusch-Marrain R, DeFronzo RA: Impairment of insulin mediated glucose metabolism by hyperosmolality in man. Diabetes 32:1028--1034, 1983 23. Brown MJ, Brown DC, Murphy MB: Hypokalemia from beta-2-receptor stimulation by circulating epinephrine. N Engl J Med 309:1414-1419, 1983 24. Brunner HR, Baer L, Sealey JE, et al: The influence of potassium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects. J Clin Invest 49:2128-2138, 1970 25. Cannon PR, Frazier LE, Hughes RH: Sodium as a toxic ion in potassium deficiency. Metabolism 2:297-312, 1953 26. Clausen T: Adrenergic control of Na+-K+ homeostasis. Acta Med Scand Suppl 672:111-115, 1983 27. Clausen T, Hansen 0: Active Na-K transport and the rate of ouabain binding. The effect of insulin and other stimuli on skeletal muscle and adipocytes. J Physiol 270:415--430, 1977 28. Conn JW: Primary aldosteronism. A new clinical syndrome. J Lab Clin Med 49:6-17, 1955

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

677

29. Conn JW: Hypertension, the potassium ion and impaired carbohydrate tolerance. N Engl J Med 273:1135-1143, 1965 30. Conn JW, Rovner DR, Cohen EL: Licorice-induced pseudoaldosteronism. J Am Med Assoc 205:492-496, 1968 31. Dalakos TG, Elias AN, Anderson GH Jr, et al: Evidence for an angiotensinogenic mechanism of the hypertension of Cushing's syndrome. J. Clin Endocrinol Metab 46:114-118, 1978 32. Dawborn JK, Watson L: Effect of prolonged administration of aldosterone on potassium and magnesium metabolism in the rabbit. Med J Aust 2:304-307, 1968 33. DeFronzo RA: Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int .17:118-134, 1980 34. DeFronzo RA, Bia M: Extrarenal potassium homeostasis. In Seldin OW, Giebisch G, (eds): The Kidney: Physiology and Pathophysiology. Raven Press, NY, 1985, p 1179-1206 35. DeFronzo RA, Bia M, Birkhead G: The effect of epinephrine on potassium homeostasis. Kidney Int 20:83-91, 1981 36. DeFronzo RA, Lee R, Jones A, et al: Effect of insulinopenia and adrenal hormone deficiency on acute potassium tolerance. Kidney Int 17:586-594, 1980 37. DeFronzo RA, Sherwin RS, Dillingham M, et al: Influence of basal insulin and glucagon secretion on potassium and sodium metabolism. J Clin Invest 61:472-479, 1978 38. DeFronzo RA, Taufield PA, Black H, et al: Impaired renal tubular potassium secretion in sickle cell disease. Ann Intern Med 90:310-316, 1979 39. Diezi J, Michoud P, Aceves J, et al: Micropuncture study of electrolyte transport across papillary collecting duct of the rat. Am J Physiol 224:623-634, 1973 40. Edelman IS, Liebman J: Anatomy of body water and electrolytes. Am J Med 27:256277, 1959 41. Epstein FH: Signs and symptoms of electrolyte disorders. In Maxwell MH, Kleeman CR (eds): Clinical Disorders of Fluid and Electrolyte Metabolism, 3 ed. McGraw-Hill, NY, 1980, p 499-530 42. Fourman P, Hervey GR: An experimental study of oedema in potassium defiCiency. Clin Sci 14:75-79, 1955 43. Fraley OS, Adler S: Isohydric regulation of plasma potassium by bicarbonate in the rat. Kidney Int 9:333-343, 1976 44. Fraley OS, Adler S: Correction of hyperkalemia by bicarbonate despite constant blood pH. Kidney Int 12:354-360, 1977 45. Gabow PA, Peterson LN: Disorders of potassium metabolism. In Schrier RW (ed): Renal and Electrolyte Disorders, 2 ed. Little, Brown, Boston, 1980, p 183-221 46. Gardner LI, Talbot NB, Cook CD, et al: The effect of potassium deficiency on carbohydrate metabolism. J Lab Clin Med 35:592-602, 1950 47. Gerstein A, Kleeman C, Gold E, et al: Aldosterone deficiency in chronic renal failure. Nephron 5:90-105, 1968 48. Ghose RR, Jivan HR: Transient urinary tract dilatation associated with hypokalemia. Brit Med J 290:1319-1320, 1985 49. Giebisch G: Physiology of potassium metabolism. In Whelton PK, Whelton A, Walker WG (eds): Potassium in Cardiovascular and Renal Medicine. Kidney Disease, Vol 6. Marcel Dekker, NY, 1986, p 3-22 50. Gill JR J r: Potassium-losing tubulopathies: Bartter's syndrome and similar disorders. In Whelton PK, Whelton A, Walker WG (eds): Potassium in Cardiovascular and Renal Medicine. Kidney Disease, Vol 6. Marcel Dekker, NY, 1986, p 121-131 51. Gill JR, Bartter FC: Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter's syndrome. Am J Med 65:766-772, 1978 52. Goldfarb S, Strunk B, Singer I, et al: Paradoxical glucose induced hyperkalemia: Combined aldosterone and insulin deficiencies. Am J Med 59:744-750, 1975 53. Gonzalez JJ, Owens W, Ungaro PC, et al: Clay ingestion: A rare cause of hypokalemia. Ann Intern Med 97:65--66, 1982 54. Goodhart GL, Handelsman S: Gentamicin and hypokalemia. Ann Intern Med 103:645--646, 1985 55. Goodkin DA, Narins RG: Quantitation of serum potassium changes during acute acid-

678

MICHAEL

A.

LINSHAW

base disturbances. In Whelton PK, Whelton A, Walker W (eds): Potassium in Cardiovascular and Renal Medicine. Kidney Disease, Vol 6. Marcel Dekker, NY, 1986, p 67-83 56. Goodman AD, Vagnucci AG, Hartroft PM: Pathogenesis of Bartter's syndrome. N Engl J Med 281:1435-1439, 1969 57. Gorden P: Glucose intolerance with hypokalemia: Failure of short-term potassium depletion in normal subjects to reproduce the glucose and insulin abnormalities of clinical hypokalemia. Diabetes 22:544-551, 1973 58. Graham DY: Effectiveness and tolerance of "solid" vs. "liquid" potassium replacement therapy. In Whelton PK, Whelton A, Walker WG (eds): Potassium in Cardiovascular and Renal Medicine. Kidney Disease, Vol 6. Marcel Dekker, NY, 1986, P 435-450, 1986 59. Greger R, Schlatter E: Properties of the basolateral membrane of the cortical thick ascending limb of Henle's loop ofrabbit kidney. A model for secondary active chloride transport. Pflugers Arch 396:325-334, 1983 59a. Hiatt N, Chapman LW, Davidson MB: Influence of epinephrine and propranolol on member K transfer in anuric dogs with hyperkalemia. J Pharmacol Exp Ther 209:282-286, 1979 60. Hirsch OJ, Hayslett JP: Adaptation to potassium. News in Physiological Sciences 1:54-57, 1986 61. Hogan MJ, Schambelan M, Biglieri EG: Concurrent hypercortisolism and hypermineralocorticoidism. Am J Med 62:777-782, 1977 62. Hollander W, Winters RW, Williams F, et al: Defect in the renal tubular reabsorption of water associated with potassium-depletion in rats. Am J PhysioI189:557-563, 1957 63. Jamison RL, Bennett CM, Berliner RW: Countercurrent multiplication by the thin loops of Henle. Am J Physiol 212:357-366, 1967 64. Jones JW, Sebastian A, Hulter HN, et al: Systemic and renal acid-base effects of chronic dietary potassium depletion in humans. Kidney Int 21:402-410, 1982 65. Kassirer JP, Schwartz WB: The response of normal man to selective depletion of hydrochloric acid: Factors in the genesis of persistent gastric alkalosis. Am J Med 40:10-18, 1966 66. Kem DC, Weinberger MH, Mayes OM et al: Saline suppression of plasma aldosterone in hypertension. Arch Int Med 128:380-386, 1971 67. Kim WG, Brown EB: Potassium transfer with constant extracellular pH. J Lab Clin Med 71:678-685, 1968 68. Kirkegaard P, Lundberg JM, Poulsen SS, et al: Vasoactive intestinal polypeptidergic nerves and Brunner's gland secretion in the rat. Gastroenterology 81:872-878, 1981 69. Knochel JP: Neuromuscular manifestations of electrolyte disorders. Am J Med 72:521-535, 1982 70. Knochel JP, Dotin LN, Hamburger RJ: Pathophysiology of intense physical conditioning in hot climate: 1. Mechanism of potassium depletion. J Clin Invest 51:242-255, 1972 71. Knochel JP, Schlein EM: On the mechanism of rhabdomyolysis in potassium depletion. J Clin Invest 51:1750-1758, 1972 72. Koht A, Cerullo LJ, Land PC, et al: Serum potassium levels during prolonged hypothermia. Anesthesiology 51:S203, 1979 73. Kornberg A, Endicott KM: Potassium deficiency in the rat. Am J PhysioI145:291-298, 1946 74. Kreisberg RA: Diabetic ketoacidosis: New concepts and trends in pathogenesis and treatment. Ann Intern Med 88:681-695, 1978 75. Kunin AS, Surawicz B, Sims EAH: Decrease in serum potassium concentrations and appearance of cardiac arrhythmias during infusion of potassium with glucose in potassium-depleted patients. N Engl J Med 266:228-233, 1962 76. Lawson DH, Murray RM, Parker JLW: Early mortality in the megaloblastic anaemias. Q J Med 41:1-14, 1972 77. Layzer RB: Periodic paralysis and the sodium-potassium pump. Ann Neurolll:547-552, 1982 78. Lewi Z, Bar Khayim Y: Food poisoning from barium carbonate. Lancet 2:342-343, 1964 79. Linshaw MA, Harrison HL, Gruskin AB et al: Hypochloremic alkalosis in infants associated with soy protein formula. J Pediatr 96:635-640, 1980 80. Lubin M: Intracellular potassium and control of protein synthesis. Fed Proc 23:994-1001, 1964

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

679

81. McFadzean AJS, Yeung R: Periodic paralysis complicating thyrotoxicosis in the Chinese. Br Med J 1:451-455, 1967 82. Makoff DL, DaSilva JA, Rosenbaum BJ, et al: Hypertonic expansion: Acid-base and electrolyte changes. Am J Physiol 218:1201-1207, 1970 83. Mantero F, Armanini D, Opocher G, et al: Mineralocorticoid hypertension due to a nasal spray containing alpha-Huro-prednisolone. Am J Med 71:352-357; 1981 83a. Martin RS, Panese S, Virginillo M, et al: Increased secretioh of potassium in the rectum of humans with chronic renal failure. Am J Kid Dis 8:105-110, 1986 84. Moore RD: Effect of insulin upon the sodium pump in frog skeletal muscle. J Physiol 232:23-45, 1973 85. Moore RD: Stimulation of Na:H exchange by insulin. Biophys J 33:203--210, 1981 86. Moore RD: Effects of insulin upon ion transport. Biochim Biophys Acta 737:1-49, 1983 87. Morerlil M, Murphy C, Goldsmith C: Increase in serum potassium resulting from the administration of hypertonic mannitol and other solutions. J Lab Clin Med 73:291-294, 1969 88. Mortimore GE: Effect of insulin on pofllssium transfer in isolated rat liver. Am J physiol 200:1315-1319, 1961 89. Naparstek Y, Gutman A: Spurious hypokalemia in myeloproliferative disorders. Am J Med Sci 288:175-177, 1984 90. National Research Council, National Academy of Sciences. Recommended Dietary Allowances, Ninth Revised Edition, Washingtori, D.C. 1980, p 169--177 91. New MI, Seaman MP: Secretion rates of cortisol and aldosterone precursors in various forms of congenital adrenal hyperplasia. J Clin Endocrinol Metab 30:361-371, 1970 92. Nicholis GL, Kahn T, Sanchez A, et at: Glucose-induced hyperkalemia in diabetic subjects. Arch Intern Med 141:49--53, 1981 93. O'Brien lAD, Fitzgerald J, Lewin IG, et al: Hypokalemia due to salbutamol overdosage. Br Med J 1:1515-1516, 1981 94. Paller MS, Douglas JG, Linas SL: Mechanism of decreased vascular reactivity to angiotensin II in conscious potassium deficient rats. J Clin Invest 73:79--86, 1984 95. Perez GO, Oster JR, Vruimonde CA: Serum potassium concentration in acidemic states. , Nephron 27:233--243, 1981 96. Petersen KA, Schulter KJ, Kerp L: Regulation of serum potassium during insulininduced hypoglycemia. Diabetes 31:615-617, 1982 97. Popp J, Achtenberg J, Cryer PE: Hyperkalemia and hyperglycemic increments in plasma potassium in diabetes mellitus. Arch Int Med 140:1617-1621, 1980 98. Rao TLK, Mathru M, Salem MR, et al: Serum potassium levels follOwing transfusion of frozen erythrocytes. Anesthesiology 52:170-172, 1980 99. ReIman AS, Schwartz WB: .The nephropathy of potassium depletion: A clinical and pathological entity. N Engl J Med 255:195-203, 1956 100. Reza MJ, Kovick RB, Shine KI, et al: Massive intravenous digoxin overdosage. N Engl J Med 291:777-778, 1974 101. Robertson GL, Aycinena P, Zerbe RL: Neurogenic disorders of osmoregulation. Am J Med 72:339-353, 1982 102. Rogers EM, Cheng LC, Zierler K: Beta adrenergic effect on Na+-K+ transport in rat skeletal muscle. Biochem Biophys Acta 464:347-355, 1977 103. Rogers TA, Wachenfeld AE: Effect of physiologic acids on electrolytes in rat diaphragm. Am J Physiol 193:623--626, 1958 104. Rogers WJ, Russell RO, McDani!l1 HG, et al: Acute effects of glucose-insulin-potassium infusion on myocardial substrates, coronary blood How and oxygen consumption in man. Am J CardioI40:421-428, 1977 lOS. Rosa RM, Silva P, Young JB, et al: Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 302:431-434, 1980 106. Rose BD: Clinical Physiology of Acid-Base and Electrolyte Disorders, 2 ed. McGrawHill, NY, 1984, pp 248-268, 567-578, 579--616 107. Rostand SG: Profound hypokaleinia in continuous ambulatory peritoneal dialysis. Arch Intern Med 143:377-378, 1983 108. Rouffignac C de, Morel F: Micropuncture study of water, electrolytes and urea movements along the loops of Henle in psammomys. J Clin Invest 48:474-486, 1969 109. Rubini ME: Water excretion in potassium deficient man. J Clin Invest 40:2215-2224, 1961

680

MICHAEL A. LINSHAW

110. Rudman D, Millikan WJ, Richardson TJ, et al: Elemental balances during intravenous hyperalimentation of underweight adult subjects. J Clin Invest 55:94--104, 1975 110a. Schwartz IL, Thaysen JH: Excretion of sodium and potassium in human sweat. J Clin Invest 35:114--120, 1956 111. Schwartz WB, Orning KJ, Porter R: The internal distribution of hydrogen ions with varying degrees of metabolic acidosis. J Clin Invest 36:373-382, 1957 112. Schwartz WB, Reiman AS: Metabolic and renal studies in chronic potassium depletion resulting from overuse of laxatives. J Clin Invest 32:258-271, 1953 113. Schwartz WB, Reiman AS: Effects of electrolyte disorders on renal structure and function. N Engl J Med 276:383-389, 1967 114. Scribner BH, Burnell JM: Interpretation of the serum potassium concentration. Metabolism 5:468-479, 1956 115. Sebastian A, Hernandez RE, Schambelan M: Disorders of renal handling of potassium. In Brenner BM, Rector FC Jr (eds): The Kidney, ed. 3. WB Saunders, Philadelphia, 1986, p 519-549 116. Sebastian A, McSherry E, Morris RC Jr: On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (Type 2 RTA). J Clin Invest 50:231-243, 1971 117. Seldin DW, Welt LG, Cort JH: The role of sodium salts and adrenal steroids in the production of hypokalemic alkalosis. Yale J Bioi Med 29:229-247, 1956 118. Shapiro W, Taubert K: Hypokalemia and digoxin-induced arrhythmias. Lancet 2:604--605, 1975 119. Shils ME: Experimental human magnesium depletion. Medicine 48:61-85, 1969 120. Simmons DH, Avedon M: Acid-base alterations and plasma potassium concentration. Am J PhysioI197:319-326, 1959 121. Squires RD, Huth EJ: Experimental potassium depletion in normal human subjects. I. Relation of ionic intakes to renal conservation of potassium. J Clin Invest 38:1134--1138, 1959 122. Stanton BA: Role of adrenal hormones in regulating distal nephron structure and ion transport. Fed Proc 44:2717-2722, 1985 123. Stanton BA, Biemesderfer D, Wade JB, et al: Structural and functional study of the rat distal nephron: Effects of potassium adaptation and depletion. Kidney Int 19:36-48, 1981 124. Stanton BA, Giebisch GH: Potassium transport by the renal distal tubule: Effects of potassium loading. Am J Physiol 243:F487-F493, 1982 124a. Stapleton FB, Nelson B, Vats TS, et al: Hypokalemia associated with antibiotic treatment. Am J Dis Child 130:1104-1108, 1976 125. Stems RH, Cox M, Feig PU, et al: Internal potassium balance and the control of the plasma potassium concentration. Medicine 60:339-354, 1981 126. Stetson DL, Wade JB, Giebisch G: MorpholOgiC alterations in the rat medullary collecting duct follOwing potassium depletion. Kidney Int 19:45-56, 1980 127. Stokes JB: Ion transport by the cortical and outer medullary collecting tubule. Kidney Int 22:473-484, 1982 128. Streeten DHP: Periodic paralysis. In Stanbury JB, Wyngaarden JB, Frederickson DS (eds): The Metabolic Basis of Inherited Disease, 2 ed. McGraw-Hill, NY, 1966, p 905-938 129. Suki WN, Stinbaugh BJ, Frommer JP, et al: Physiology of diuretic action. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. Raven Press, NY, 1985, p 2127-2162 130. Surawciz B: Relationship between electrocardiogram and electrolytes. Am Heart' J 73:814--834, 1967 131. Tenebein M: Severe cardiac dysrhythmia from barium acetate ingestion. Ped Emer Care 1:34-36, 1985 132. Verner JV, Morrison AB: Endocrine pancreatic islet disease with diarrhea: Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med 133:492-500, 1974 133. Vogel CM, Kingsbury RJ, Baue AE: Intravenous hyperalimentation. A review of two and one-half years' experience. Arch Surg 105:414-419, 1972 134. Watten RH, Morgan FM, Songkhla YN, et al: Water and electrolyte studies in cholera. J Clin Invest 38:1879-1889, 1959

POTASSIUM HOMEOSTASIS AND HYPOKALEMIA

681

135. Welling PA, Linshaw MA, Sullivan LP: Effect of barium on cell volume regulation in rabbit proximal tubules. Am J Physiol 249:F20-F27, 1985 136. White MG: Bartter's syndrome. A manifestation of renal tubular defects. Arch Intern Med 129:41-47, 1972 136a. Winter RW: Principles of Pediatric Fluid Therapy. 2 ed. Little, Brown, Boston, 1982, pp 145-148 137. Womersley RA, Darragh JH: Potassium and sodium restriction in the normal human. J Clin Invest 34:456-461, 1955 138. Wright FS: Sites and mechanisms of potassium transport along the renal tubule. Kidney Int 11:415-432, 1977 139. Wright FS, Giebisch G: Regulation of potassium excretion. In Seldin DW, Giebisch G -(eds): The Kidney: Physiology and Pathophysiology. Raven Press, NY, 1985, p 1223-1249. 140. Zalups RK, Stanton BA, Wade JB, et al: Structural adaptation in initial collecting tubule following reduction in renal mass. Kidney Int 27:636--642, 1985 141. Zierler KL: Hyperpolarization of muscle by insulin in a glucose free environment. Am J PhysioI197:524-526, 1959 142. Zierler KL: Effect of insulin on potassium efflux from rat muscle in the presence and absence of glucose. Am J PhysioI198:1066-1070, 1968 143. Zierler K: Family periodic paralyses. In Whelton PK, Whelton A, Walker WE (eds): Potassium in Cardiovascular and Renal Medicine. Kidney Disease, Vol 6. Marcel Dekker, NY, 1986, p 133-142 144. Zierler K, Rogers EM: Rapid hyperpolarization ofrat skeletal muscle induced by insulin. Biochim Biophys Acta 640:687-692, 1981 Department of Pediatrics The University of Connecticut Health Center School of Medicine Farmington, Connecticut 06032