External potassium balance

External balance for potassium is maintained by matching output (primarily in urine) to input (from the diet). In the normal animal, potassium enters the body only through the gastrointestinal tract, and virtually all ingested potassium is absorbed in the stomach and small intestine. Transport of potassium in the small intestine is passive, whereas active transport (responsive to aldosterone) occurs in the colon. Colonic secretion of potassium may play an important role in extrarenal potassium homeostasis in some disease states (e.g., chronic renal failure) (Fig. 5-3).

Figure 5-3 Relationship between the degree of renal insufficiency and fecal potassium excretion. Data points are compiled from three studies comprising 98 balance periods in 40 human patients. Variation in dietary protein or sodium intake did not produce consistent changes in fecal potassium excretion; thus, data points from these balance periods were included without special designation.

(From Alexander EA, Perrone RD. Regulation of extrarenal potassium metabolism. In: Maxwell MH, Kleeman CR, Narins RG, editors. Clinical disorders of fluid and electrolyte metabolism, 4th ed. New York: McGraw-Hill, 1987: 105–117, with permission of the McGraw-Hill Companies.)

Potassium derived from the diet and endogenous cellular breakdown is removed from the body primarily by the kidneys and, to a much lesser extent, by the gastrointestinal tract. During zero balance, 90% to 95% of ingested potassium is excreted in urine, and the remaining 5% to 10% is excreted via the gastrointestinal tract. This pattern of output has been observed during control balance studies in normal dogs.^{12,139,152,169,182} In a study of renal handling of potassium in dogs, 90% to 98% of potassium intake was eliminated from the body by the kidneys.²⁴

Adaptation occurs during chronic potassium loading so that the animal is protected from hyperkalemia that could occur as a result of an acute potassium load. This effect results from enhanced renal and colonic excretion of potassium, as well as from enhanced uptake of potassium by the liver and muscle, mediated by the effects of insulin and catecholamines. Potassium deprivation is associated with decreased aldosterone secretion, suppression of potassium secretion in the distal nephron, and increased reabsorption of potassium in the inner medullary collecting ducts. Skeletal muscle potassium concentration decreases, but brain and heart potassium concentrations are minimally affected during potassium depletion.^20,107,178 The colon adapts to potassium deprivation by decreasing its secretion of potassium.

Internal potassium balance

Internal balance for potassium is maintained by translocation of potassium between ECF and ICF. One half to two thirds of an acute potassium load appears in the urine within the first 4 to 6 hours, and effective translocation of potassium from ECF to ICF is crucial in preventing life-threatening hyperkalemia until the kidneys have sufficient time to excrete the remainder of the potassium load. Endogenous insulin secretion and stimulation of β₂-adrenergic receptors by epinephrine promote cellular uptake of potassium in the liver and muscle by increasing the activity of cell membrane Na⁺, K⁺-ATPase. The main effects of these hormones are to facilitate distribution of an acute potassium load and not to mediate minor adjustments in serum potassium concentration. The ECF concentration of potassium itself plays an important role in translocation because potassium movement into cells is facilitated by the change in chemical concentration gradient resulting from addition of potassium to ECF. The fraction of an acute potassium load taken up by the body is increased during chronic potassium depletion and decreased when total body potassium is excessive. In summary, any change in serum potassium concentration must arise from a change in intake, distribution, or excretion (Fig. 5-4).

Figure 5-4 Components of potassium homeostasis. ECF, Extracellular fluid; ICF, intracellular fluid.

(Drawing by Tim Vojt.)

Effect of acid-base balance on potassium distribution

The effect of acute pH changes on translocation of potassium between ICF and ECF is complex. In general, acidosis is associated with movement of potassium ions from ICF to ECF, and alkalosis is associated with movement of potassium ions from ECF to ICF. Early animal studies and observations in a small number of human patients led to the prediction that acute metabolic acidosis would be associated with a 0.6-mEq/L increment in serum potassium concentration for each 0.1-U decrement in pH. This rule of thumb has circulated widely among clinicians.^31,181,188

However, a critical review of experimental studies in animals and humans demonstrated that changes in serum potassium concentration during acute acid-base disturbances were quite variable.⁴ The change in serum potassium concentration was greatest during acute mineral acidosis. In dogs, the increase in serum potassium concentration after administration of a mineral acid (e.g., HCl or NH₄Cl) was very variable, ranging from a 0.17- to 1.67-mEq/L increment in serum potassium concentration per 0.1-U decrement in pH (mean, 0.75 mEq/L). The increment in serum potassium concentration during acute respiratory acidosis in dogs was much lower, averaging only 0.14 mEq/L per 0.1-U decrement in pH. The decrement in serum potassium concentration during metabolic alkalosis in dogs averaged 0.18 mEq/L per 0.1-U increment in pH, whereas it averaged 0.27 mEq/L per 0.1-U increment in pH during respiratory alkalosis. In another study, respiratory alkalosis induced by hyperventilation in anesthetized dogs caused a somewhat greater decrement in serum potassium concentration (0.4 mEq/L) for each 0.1-U increment in pH.¹³⁶ An increase in serum potassium concentration did not occur in acute metabolic acidosis caused by organic acids (e.g., lactic acid and ketoacids).* Acute infusion of β-hydroxybutyric acid in normal dogs caused an increase in insulin in portal venous blood and hypokalemia, presumably as a result of potassium uptake by cells. Conversely, acute infusion of HCl led to increased portal vein glucagon concentration and hyperkalemia, possibly caused by potassium release from cells.⁵ In summary, only mineral acidosis is expected to cause any clinically relevant change in serum potassium concentration during acute acid-base disturbances.

Many factors probably contribute to the variable changes observed in serum potassium concentration during acute acid-base disturbances, including blood pH and HCO₃⁻ concentration, nature of the acid anion (mineral versus organic), osmolality, hormonal activity (e.g., catecholamines, insulin, glucagon, and aldosterone), and the metabolic and excretory roles of the liver and kidneys.⁴ Hyperosmolality and lack of insulin are more likely to be responsible for hyperkalemia observed in patients with diabetic ketoacidosis than is the acidosis itself.

Hyperkalemia associated with acute metabolic acidosis induced by mineral acids is transient. In a study of acute and chronic metabolic acidosis induced in dogs by administration of HCl or NH₄Cl, hyperkalemia was observed after acute infusion of HCl, but hypokalemia developed after 3 to 5 days of NH₄Cl administration.¹²² The observed hypokalemia was associated with inappropriately high urinary excretion of potassium and increased plasma aldosterone concentration.¹²² Similar findings have been reported in rats with chronic metabolic acidosis induced by NH₄Cl. Despite a total body deficit of potassium, rats with chronic metabolic acidosis did not conserve potassium appropriately.¹⁷⁰ This effect may be caused by a decreased filtered load of HCO₃⁻, increased distal delivery of sodium, and increased distal tubular flow. Thus, metabolic acidosis of at least 2 to 3 days’ duration is associated with increased urinary potassium excretion and mild hypokalemia rather than hyperkalemia.⁷⁹

Mechanisms of renal tubular transport of potassium

The transepithelial electrical potential difference is lumen negative in the early proximal tubule, but no active transport mechanism for potassium has been discovered in this segment of the nephron. In the proximal tubule, potassium is reabsorbed along with water by solvent drag via the paracellular route. Apparently, water reabsorption increases the luminal concentration of potassium enough to overcome the unfavorable transepithelial potential difference. The transepithelial electrical potential difference becomes lumen positive in the late proximal tubule, and this facilitates reabsorption of potassium by the paracellular route. Transcellular transport of potassium in the proximal tubular cells occurs by means of potassium channels in both luminal and basolateral membranes and by a K⁺-Cl⁻ cotransporter in basolateral membranes (Fig. 5-5).

Figure 5-5 Renal tubular transport mechanisms for potassium in the proximal tubule.

TEPD, Transepithelial potential difference. (Drawing by Tim Vojt.)

In the thick ascending limb of the Henle loop, the transepithelial electrical potential difference is strongly lumen positive, and most potassium reabsorption occurs by the paracellular route. Potassium channels in the luminal membranes allow potassium to exit the cell down its concentration gradient and facilitate the electrochemical gradient for potassium reabsorption via the paracellular route. Transcellular reabsorption of potassium is facilitated by the luminal Na⁺-K⁺-2Cl⁻ cotransporter and by potassium channels and a K⁺-Cl⁻ cotransporter in the basolateral membranes (Fig. 5-6).

Figure 5-6 Renal tubular transport mechanisms for potassium in the thick ascending limb of Henle’s loop. TEPD, Transepithelial potential difference.

(Drawing by Tim Vojt.)

The mechanisms of renal potassium handling in the distal convoluted tubule are shown in Figure 5-7. The thiazide-sensitive Na⁺-Cl⁻ cotransporter and the K⁺-Cl⁻ cotransporter in the luminal membranes of these tubular cells result in secretion of potassium and reabsorption of sodium while chloride is recycled across the luminal membrane. The basolateral Na⁺, K⁺-ATPase maintains a low intracellular concentration of sodium and a high intracellular concentration of potassium that facilitate sodium reabsorption and potassium secretion across the luminal membranes.

Figure 5-7 Renal tubular transport mechanisms for potassium in the distal convoluted tubule (early distal tubule).

TEPD, Transepithelial potential difference. (Drawing by Tim Vojt.)

Principal cells are found in the connecting tubule and collecting duct and are responsible for potassium secretion. The basolateral membranes of principal cells are rich in Na⁺, K⁺-ATPase, which maintains a high intracellular potassium concentration. The luminal membranes of the principal cells contain an electrogenic sodium channel (ENaC). This sodium channel is directly blocked by the diuretics amiloride and triamterene, whereas spironolactone antagonizes the effect of aldosterone on the channel. Sodium movement through this channel renders the tubular lumen negative, and the resultant increase in lumen electronegativity facilitates secretion of K⁺ ions through luminal K⁺ channels (Fig. 5-8).

Figure 5-8 Renal tubular transport mechanisms for potassium in the principal cells of the late distal tubule and collecting duct.

TEPD, Transepithelial potential difference. (Drawing by Tim Vojt.)

There are two types of intercalated cells in the distal nephron. Type A or α intercalated cells contain H⁺-ATPase and H⁺, K⁺-ATPase in their luminal membranes and Cl⁻- HCO₃⁻ countertransporters and Cl⁻ and K⁺ channels in their basolateral membranes. They also contain carbonic anhydrase. This arrangement allows the intercalated cell to secrete H⁺ ions and reabsorb K⁺ and HCO₃⁻ ions. Potassium is actively transported across the luminal membranes of type α intercalated cells by H⁺, K⁺-ATPase and then diffuses down its concentration gradient through potassium channels in the basolateral membranes (Fig. 5-9). Type A and α intercalated cells are found in the connecting tubule, cortical collecting duct, and outer medullary collecting duct. Type B and β intercalated cells are found only in the cortical collecting ducts and secrete HCO₃⁻ ions. They are able to do so because their polarity is reversed as compared with type α intercalated cells (i.e., the H⁺-ATPase is in the basolateral membrane, and the Cl⁻- HCO₃⁻ countertransporter is in the luminal membrane).

Figure 5-9 Renal tubular transport mechanisms for potassium in the α intercalated cells of the late distal tubule and collecting duct.

CA, Carbonic anhydrase; TEPD, Transepithelial potential difference. (Drawing by Tim Vojt.)

Potassium is reabsorbed from the last portion of the outer medullary collecting duct and throughout the inner medullary collecting duct. In these segments of the nephron, potassium is reabsorbed by the paracellular route despite a lumen-negative transepithelial potential difference, because reabsorption of water increases the chemical concentration gradient sufficiently to overcome the unfavorable electrical gradient.

Determinants of urinary potassium excretion

Three main factors affect potassium secretion in the distal nephron: the magnitude of the chemical concentration gradient for potassium between the tubular cells and tubular lumen, the tubular flow rate, and the transmembrane potential difference across the luminal membranes of the tubular cells. Gastrointestinal absorption of a potassium load increases the ECF concentration of potassium. This results in an increase in the number of K⁺ ions available for uptake at the basolateral membranes of the distal tubular cells by Na⁺, K⁺-ATPase, and the resulting increase in intracellular potassium concentration increases the chemical concentration gradient for diffusion of K⁺ ions out of the tubular cells across their luminal membranes.

Aldosterone is the most important hormone affecting urinary potassium excretion. Its secretion by the zona glomerulosa of the adrenal gland is stimulated directly by hyperkalemia and angiotensin II (produced in response to volume depletion), whereas adrenocorticotropic hormone (ACTH), hyponatremia, and decreased extracellular pH play permissive roles in promoting aldosterone secretion. Aldosterone release is inhibited by dopamine and atrial natriuretic factor, both of which are released in response to volume expansion.

Aldosterone increases reabsorption of Na⁺ and secretion of K⁺ and H⁺ ions in the distal nephron. Its primary effect is to increase the number of open Na⁺ channels in the luminal membranes of the principal cells. Sodium reabsorption via these luminal Na⁺ channels is electrogenic (i.e., it generates electronegativity in the tubular lumen). This electronegativity can be dissipated either by K⁺ or H⁺ ion secretion or by Cl⁻ reabsorption in the distal nephron. Aldosterone increases the activity and number of Na⁺, K⁺-ATPase pumps in the basolateral membranes of the principal cells, and this effect may occur as a result of increased entry of Na⁺ ions across the luminal membranes. Increased Na⁺, K⁺-ATPase activity in turn increases the intracellular K⁺ concentration and facilitates K⁺ secretion across the luminal membranes. Aldosterone also increases the number of open K⁺ channels in the luminal membrane, thus facilitating K⁺ exit into tubular fluid.

Aldosterone can influence H⁺ secretion in two ways. It directly promotes H⁺ ion secretion in H⁺-secreting type α intercalated cells by stimulation of the H⁺-ATPase present in their luminal membranes. Aldosterone also promotes H⁺ secretion in the distal tubule by stimulating electrogenic Na⁺ reabsorption in principal cells and increasing lumen electronegativity, which favors enhanced H⁺ secretion.

An increase in distal tubular flow enhances potassium secretion by rapidly moving secreted K⁺ ions downstream and providing new tubular fluid from upstream in the nephron. This allows maintenance of a high chemical concentration gradient for potassium secretion and provides a “sink” for movement of K⁺ ions into tubular fluid. A decrease in distal tubular flow has the opposite effect and promotes dissipation of the chemical gradient for diffusion of K⁺ ions from principal cells into tubular fluid.

Lumen electronegativity is generated by sodium reabsorption through Na⁺ channels in the luminal membranes of principal cells. Normally, some of this electronegativity is dissipated by passive Cl⁻ reabsorption. If a large concentration of a relatively nonresorbable anion (e.g., SO₄²⁻, HCO₃⁻, penicillin) is present in distal tubular fluid, less dissipation of the electronegativity occurs, and K⁺ secretion is enhanced. This factor contributes to the pathophysiology of metabolic alkalosis. In this setting, there is less Cl⁻and more HCO₃⁻ in the distal tubular fluid, and HCO₃⁻ is relatively nonresorbable in the cortical collecting duct. This is one reason metabolic alkalosis promotes urinary K⁺ excretion. Amiloride is a diuretic that impairs luminal Na⁺ entry into principal cells by decreasing the number of open Na⁺ channels. This in turn reduces lumen electronegativity and impairs K⁺ secretion. Thus, the magnitude of distal tubular lumen electronegativity has an important effect on urinary K⁺ excretion.

The Na⁺ and Cl⁻ concentrations of distal tubular fluid usually have little effect on K⁺ secretion. When the luminal Na⁺ concentration is very low (<25 to 35 mEq/L), however, diffusion of Na⁺ ions into distal tubular cells may be impaired sufficiently to produce an increase in the tubular cell transmembrane potential (making the cell interior more negative) and impeding diffusion of K⁺ ions from the cell into the tubular lumen.^85,204,205 Extremely low luminal Cl⁻ concentrations (<10 mEq/L) may increase net potassium secretion, possibly because some fraction of K⁺ reabsorption or secretion may be accomplished by K⁺-Cl⁻ cotransport.¹⁹⁸ Such a mechanism may also play a role in the pathophysiology of enhanced urinary K⁺ excretion during metabolic alkalosis. Antidiuretic hormone (ADH) helps minimize disruption of potassium balance during water deprivation by increasing the number of open luminal K⁺ channels in principal cells and facilitating potassium excretion at a time when distal tubular flow is reduced.^36,69,183 Conversely, potassium excretion is not necessarily increased despite increased distal tubular flow during water diuresis because ADH is suppressed. Major factors affecting renal excretion of potassium are summarized in Figure 5-10.

Figure 5-10 Factors affecting urinary excretion of potassium.

(Drawing by Tim Vojt.)

Factors influencing renal potassium excretion

Clinical and laboratory features

Many dogs and cats with hypokalemia have no clinical signs. Muscular weakness, polyuria, polydipsia, and impaired urinary concentrating capacity are the clinical signs most likely to be recognized in dogs and cats with symptomatic hypokalemia. The pathophysiology of these clinical signs is discussed here.

The clinician should verify the abnormal serum potassium concentration with the laboratory, but measurement of potassium by flame photometry and ion-selective potentiometry is reliable, and errors are uncommon. The clinical history often provides information about the likely source of potassium loss (e.g., chronic vomiting and diuretic administration) or the possibility of translocation (e.g., insulin administration and alkalosis).

Determination of the fractional excretion of potassium (FE_K) may help differentiate between renal and nonrenal sources of potassium loss. Fractional potassium excretion can be calculated and expressed as a percentage using:

where U_K is the urine concentration of K (mEq/L), S_K is the serum concentration of K (mEq/L), U_Cr is the urine concentration of creatinine (mg/dL), and S_Cr is the serum concentration of creatinine (mg/dL).

The FE_K should be less than 4% for nonrenal sources of loss, and in the presence of hypokalemia, values above 4% may indicate inappropriate renal loss.⁶⁰ In one study, however, FE_K values for normal cats were 10.6 ± 2.1%.³ In another study of normal cats receiving a potassium-deficient diet, FE_K values decreased from 10% to 12% to 3% to 6%.⁶¹ Thus, FE_K values up to 6% should probably be considered normal in potassium-depleted animals with normal renal function. However, the clinical utility of FE_K calculations is limited by the fact that FE_K does not correlate well with 24-hour urinary excretion of potassium.^3,74 The occurrence of hypokalemia in patients with metabolic alkalosis suggests vomiting of stomach contents or diuretic administration as likely causes of potassium loss. In patients with hypokalemia and metabolic acidosis, diarrhea caused by small intestinal disease, chronic renal failure, and distal renal tubular acidosis are more likely causes of potassium loss (Fig. 5-11).

Figure 5-11 Algorithm for the clinical approach to hypokalemia.

(Drawing by Tim Vojt.)

The effect of aldosterone on serum potassium excretion can also be evaluated by comparing urine and serum potassium concentrations after correcting the urine potassium concentration for reabsorption of solute-free water by the kidneys. This index has been called the transtubular potassium gradient (TTKG).^{39,122,204,205} A value of 5.0 or higher has been said to indicate the presence of an aldosterone effect, whereas a value of 3.0 or less is expected in the absence of mineralocorticoid activity.²⁰⁵ Use of the TTKG is valid only when the urine osmolality is greater than 300 mOsm/kg and the urine sodium concentration is greater than 25 mEq/L. The renal TTKG may be estimated according to the equation:

where U_K is the urine potassium concentration (mEq/L), S_K is the serum potassium concentration (mEq/L), U_Osm is the urine osmolality (mOsm/kg), and S_Osm is the serum osmolality (mOsm/kg).^204,205 Values for TTKG were estimated as 3.7 ± 0.9 in normal cats and 4.2 ± 1.3 in normal dogs.^52,56 Determination of TTKG was used in a dog with hypoadrenocorticism to assess the contribution of concurrent trimethoprim administration on the observed hyperkalemia.¹⁶⁶ The causes of hypokalemia are listed in Box 5-1, and the diagnostic approach to hypokalemia is presented in Figure 5-11.

Specific causes of hypokalemia in dogs and cats

Hypokalemia arises from decreased intake, translocation of potassium from ECF to ICF, and excessive loss of potassium by either the gastrointestinal or urinary route. Decreased intake of potassium alone is unlikely to cause hypokalemia, but it may be a contributing factor. In chronically ill animals, for example, prolonged anorexia, loss of muscle mass, and ongoing urinary potassium losses probably combine to cause hypokalemia. A specific cause for mild hypokalemia in hospitalized dogs and cats often cannot be identified. Such hypokalemia may resolve with successful treatment of the primary disease process. Iatrogenic hypokalemia may develop when potassium-deficient fluids are administered to anorexic patients in a hospital setting. For example, lactated Ringer’s solution (potassium concentration, 4 mEq/L) is a replacement solution and does not provide sufficient potassium for maintenance needs in most animals. Solutions used for maintenance fluid therapy should contain 15 to 30 mEq/L potassium (see Chapter 14). Ingestion of certain types of clay has been associated with hypokalemia in humans because the clay can bind potassium in the gastrointestinal tract and impair its absorption, and hypokalemia has been reported in a cat after ingestion of clay cat litter containing bentonite.^18,84,96

Translocation of potassium into cells may occur with alkalemia, insulin release, and catecholamine release. Alkalemia contributes to hypokalemia as K⁺ ions enter cells in exchange for H⁺ ions. Insulin promotes uptake of glucose and potassium by hepatic and skeletal muscle cells and may contribute to hypokalemia when glucose-containing fluids are administered. The stress of illness and the associated epinephrine release may also contribute to hypokalemia. Severe hypokalemia has been reported in dogs that have ingested the β₂-adrenergic agonist albuterol.^129,200 The mechanism of hypokalemia was presumably rapid uptake of extracellular potassium by liver and muscle cells. Hypokalemia has been associated with hypothermia, possibly as a result of potassium entry into cells.¹⁶⁴ Mild hypokalemia was reported in 78% of dogs suffering from rattlesnake envenomation.²⁸ Affected dogs also had transient echinocytosis that was not consistently associated with the observed hypokalemia.

A syndrome characterized by recurrent episodes of limb muscle weakness, neck ventroflexion, increased creatine kinase concentrations, and hypokalemia has been reported in related Burmese cats 4 to 12 months of age.^{22,103,112,127,128} This syndrome may represent an animal model of hypokalemic periodic paralysis in humans, a familial disorder characterized by episodes of sudden translocation of potassium from ECF to ICF.

Gastrointestinal loss of potassium (e.g., vomiting of stomach contents) is an important cause of hypokalemia in small animals. In one study, hypokalemia was present in 25% of dogs with gastrointestinal foreign bodies and occurred in association with hypochloremia, metabolic alkalosis, and hyponatremia.²³ Chloride depletion and sodium avidity related to volume depletion contribute to perpetuation of potassium depletion and metabolic alkalosis in this setting by enhancing urinary losses of K⁺ and H⁺ ions. The effects of metabolic alkalosis on potassium balance are discussed further in Chapter 10.

Urinary loss of potassium is another important cause of hypokalemia, and hypokalemia is common in cats with chronic renal failure. Approximately 20% to 30% of cats with chronic renal failure have hypokalemia at presentation, and in one study, chronic renal disease was the most common associated disorder observed in a survey of cats with hypokalemia.^54,60,64,116 Most dogs with chronic renal failure have normal serum potassium concentrations. For example, fewer than 10% of dogs with chronic renal failure caused by renal amyloidosis had hypokalemia at presentation.⁵⁵ Hypokalemia also commonly occurs during the postobstructive diuresis that follows relief of urethral obstruction in cats with idiopathic lower urinary tract disease.

Renal tubular acidosis may be associated with hypokalemia (see Chapter 10). In distal (type I) renal tubular acidosis, hypokalemia is usually present before treatment, and urinary potassium losses may result in part from increased aldosterone secretion. Hypokalemia has been reported in distal renal tubular acidosis in cats.^62,197,202 In proximal (type II) renal tubular acidosis, correction of acidosis requires large doses of NaHCO₃, and hypokalemia usually appears during therapy. This is a result of the increased delivery of Na⁺ and HCO₃⁻ ions to the distal nephron. These factors enhance urinary potassium excretion by increasing distal tubular flow and lumen electronegativity (HCO₃⁻ is a relatively nonresorbable anion in the cortical collecting duct).

Finally, hypokalemic nephropathy characterized by chronic tubulointerstitial nephritis may develop in cats fed diets low in potassium and containing urinary acidifiers.^{30,56,57,58,60} Stimulation of aldosterone secretion by chronic metabolic acidosis and decreased gastrointestinal absorption of potassium may contribute to potassium depletion in this syndrome.^61,170

Mutations in genes that encode epithelial transport proteins and channels have been associated with rare disorders of renal tubular function that cause hypokalemia in humans. One of these familial disorders, Bartter syndrome, is especially complex. It can be caused by mutations in the NKCC2 gene that codes for the luminal Na^+/- K⁺-2Cl⁻ cotransporter found in the thick ascending limb of Henle’s loop (type I), in the gene for the ROMK protein component of renal tubular potassium channels (type II), in the CLCNKB gene that codes for the ClC-Kb chloride channel in the basolateral membranes of tubular cells in the thick ascending limb (type III), or in the BSND gene that codes for barttin, a subunit protein of chloride channels that is required for proper insertion of the channels into the basolateral membrane (type IV).^94,176 Other rare diseases can arise from a loss of function mutation in the NCCT gene for the thiazide-sensitive Na⁺-Cl⁻ cotransporter in the luminal membranes of the distal convoluted tubule (Gitelman’s variant of Bartter syndrome) or a gain of function mutation in the SCNN1 gene for the luminal sodium channel (ENaC) of the principal cells of the collecting duct (Liddle syndrome). None of these rare tubular disorders has yet been recognized in veterinary medicine.

Mineralocorticoid excess is a relatively uncommon cause of urinary potassium loss and hypokalemia in dogs and cats. One report described hyperaldosteronism in a dog thought to be caused by adrenal hyperplasia of the adrenal zona glomerulosa.²⁶ Older dogs with hyperaldosteronism as a result of aldosterone-producing adenomas or adenocarcinomas are presented for evaluation of weakness and polyuria.^67,102,207 Mild to moderate hypertension may be detected, and hypokalemia, hypernatremia, mild metabolic alkalosis, dilute urine, and extremely high serum aldosterone concentrations (>3000 pmol/L; normal, 14 to 957 pmol/L) are present on laboratory evaluation. Dogs with adenomas respond well to surgical adrenalectomy, but those with adenocarcinomas experience recurrence of clinical signs if metastasis occurs. One affected dog had polyuria and hyperaldosteronism associated with a very small (2 mm) adrenal adenoma that initially was undetected by computed tomography, and the dog responded to treatment with spironolactone.¹⁵⁹ Ultimately, the tumor was identified and removed, and the dog recovered completely. Another dog with an adrenal adenocarcinoma had clinical and laboratory features of mineralocorticoid excess, but serum aldosterone concentration was undetectable.¹⁵⁶ Serum desoxycorticosterone concentration was measured and found to be abnormally high (288 ng/mL; normal, 16 to 46 ng/mL). After surgical removal of the tumor, serum potassium concentration normalized, but serum desoxycorticosterone concentration remained high, and the dog was treated with spironolactone.

Clinical and laboratory features of hyperaldosteronism also may be observed in dogs with hyperadrenocorticism caused by adrenal tumors that have been documented to produce a variety of steroid hormones, including aldosterone, deoxycorticosterone, and corticosterone in addition to cortisol.^{17,46,115,117,130}

Several cats (5 to 20 years of age) with hyperaldosteronism have been reported.* Affected cats are presented for evaluation of muscle weakness (sometimes with ventroflexion of the neck), ataxia, weight loss, polyuria, polydipsia, and ocular abnormalities (e.g., mydriasis, blindness, and retinal detachments) associated with hypertension. Laboratory features consist of hypokalemia, hypernatremia, mild metabolic alkalosis, increased serum creatine kinase activity, dilute urine, extremely high serum aldosterone concentrations (usually >1000 pmol/L; normal, 194 to 388 pmol/L), and plasma renin activity that is low or at the low end of the normal reference range (0.2 to 0.5 ng/L/sec; normal, 0.2 to 1.4 ng/L/sec). In two affected cats, urinary FE_K was more than 50% and consistent with inappropriate kaliuresis.⁷⁵ In these two cats, chronic renal disease also was present and might have contributed to hypertension and increased FE_K. Hyperaldosteronism may be associated with hyperglycemia caused by insulin resistance, and one affected cat had diabetes mellitus that persisted despite removal of the adrenal tumor.⁷⁵ Aldosterone-producing adrenal tumors in cats often are 1 to 3 cm in diameter and can be visualized on abdominal ultrasonography. Cytologic evaluation of fine needle aspirates is consistent with neuroendocrine neoplasia, and histologically these tumors are adenomas or adenocarcinomas. Invasion of the caudal vena cava by the tumor can result in thromboembolism.^11,75,163 Removal of adrenal tumors causing hyperaldosteronism can be successful in affected cats, but surgery carries a high risk of life-threatening intraoperative or postoperative hemorrhage.¹¹ Medical treatment with potassium supplementation (2 to 6 mEq/day), spironolactone (2 to 4 mg/kg/day) to antagonize the effects of aldosterone, and amlodipine (0.625 to 1.25 mg/day) to control hypertension and can be used to manage affected cats. Survival times of 1 to 5 years have been reported for surgical or medical management.¹¹ Concurrent hyperaldosteronism and hyperprogesteronism have been reported in a cat that also had clinical signs of hyperadrenocorticism and diabetes mellitus.²⁷ See Chapter 10 for further discussion of states of mineralocorticoid excess.

Administration of loop or thiazide diuretics may cause hypokalemia as a result of increased flow rate in the distal tubules and increased secretion of aldosterone secondary to volume depletion. In one study, dogs with heart failure receiving furosemide had significantly lower mean serum potassium concentrations (mean serum potassium concentration, 3.9 mEq/L) than did normal dogs (mean serum potassium concentration, 4.4 mEq/L) or untreated dogs with arrhythmias (mean serum potassium concentration, 4.3 mEq/L).⁴⁰ Of the dogs treated with furosemide, 17% had serum potassium concentrations less than 3.0 mEq/L. In another study, 10 dogs with congestive heart failure treated with captopril, furosemide, and a sodium-restricted diet did not develop significant changes in serum electrolyte concentrations.¹⁶⁵ Penicillin derivatives may cause hypokalemia by acting as nonresorbable anions in the distal tubule and increasing secretion of potassium into tubular fluid. Amphotericin B may cause increased loss of potassium by binding to sterols in cell membranes and increasing permeability. Peritoneal dialysis can be complicated by hypokalemia if potassium-free dialysate is used for an extended time period.⁴⁵

Treatment

Preparations available for parenteral use include KCl (2 mEq K⁺/mL) and a potassium phosphate solution containing K₂HPO₄ and KH₂PO₄ (4.36 mEq K⁺/mL). Potassium chloride is the additive of choice for parenteral therapy because chloride repletion is essential if vomiting or diuretic administration is the underlying cause of hypokalemia. Replacement of chloride is also essential for resolution of the metabolic alkalosis often present in such settings (see Chapter 10). When administered intravenously, KCl generally should not be infused at rates greater than 0.5 mEq/kg/hr to avoid potential adverse cardiac effects. A scale such as that shown in Table 5-2 may be used to estimate the amount of KCl to add to parenteral fluids based on serum potassium concentration.⁸⁸ Infusion rates greater than 0.5 mEq/kg/hr may be required to normalize serum potassium concentration in hypokalemic patients with diabetic ketoacidosis treated with insulin. In hypokalemic human patients, potassium infusion rates up to 0.9 mEq/kg/hr were used safely in one study.⁸⁹ Careful mixing of potassium chloride after addition to flexible bags of fluids is extremely important to prevent the patient from receiving a high concentration of potassium that could be life threatening. In one study, inadequate mixing of potassium chloride added to flexible bags of fluid was demonstrated to result in up to a fourfold increase in the concentration of potassium in the fluids.⁵¹ For determination of serum potassium concentration, when submitting blood samples that have been drawn from intravenous catheters in patients receiving potassium-supplemented fluids, the initial volume of blood withdrawn should be discarded, and a second sample should be submitted to the laboratory to avoid results that may be spuriously high.

Table 5-2 Guidelines for Routine Intravenous Supplementation of Potassium in Dogs and Cats

Infusion of potassium-containing fluids initially may be associated with a decrease in serum potassium concentration as a result of dilution, increased distal renal tubular flow, and cellular uptake of potassium, especially if the infused fluid also contains glucose.⁶⁰ This effect may be minimized by using a fluid that does not contain glucose, administering fluids at an appropriate rate, and beginning oral potassium supplementation as soon as possible. The concentration of potassium in the infused fluid generally should not exceed 60 mEq/L, because higher concentrations of potassium may cause pain and sclerosis of peripheral veins.¹⁶² Parenteral fluids containing up to 35 mEq/L have been used safely by the subcutaneous route.⁷²

Careful potassium supplementation is important when using insulin to treat diabetic ketoacidosis. Chronic potassium depletion is usually present in affected patients as a result of loss of muscle mass, anorexia, vomiting, and polyuria. However, serum potassium concentrations are sometimes normal or even increased because of the effects of insulin deficiency and hyperosmolality on serum potassium concentration. Because blood glucose concentration decreases with insulin treatment, marked hypokalemia may develop if supplementation is not adequate.

Potassium gluconate (e.g., Kaon and Tumil-K) is recommended for oral supplementation. In one study, orally administered KCl and KHCO₃ were not palatable to cats.⁵⁹ Dogs may require 2 to 44 mEq potassium per day, depending on body size.⁹² In cats with hypokalemic nephropathy, the initial oral dosage of potassium gluconate is 5 to 8 mEq/day divided in two or three doses, whereas the maintenance dosage can usually be reduced to 2 to 4 mEq/day.⁶⁰ It is difficult to estimate the amount of potassium required to reestablish normal balance from the serum potassium concentration in a given patient because potassium is an intracellular solute. Thus, the amount of potassium required for treatment must be determined by judicious supplementation and serial measurement of serum potassium concentration during treatment and recovery.

Clinical and laboratory features

The clinical manifestations of hyperkalemia reflect changes in cell membrane excitability and reflect the magnitude and the rapidity of onset of hyperkalemia. Muscle weakness develops with hyperkalemia, usually when serum potassium concentration exceeds 8.0 mEq/L. The electrocardiographic findings caused by hyperkalemia are often characteristic, and the electrocardiogram may be helpful in establishing a suspicion of hyperkalemia while awaiting results of the serum potassium concentration (Fig. 5-12).

Figure 5-12 Electrocardiograms of a cat and dog with hyperkalemia. A, Electrocardiogram from an 8-year-old female domestic short-haired cat with oliguric acute renal failure and serum K⁺ concentration of 7.8 mEq/L. B, Electrocardiogram of the same cat after 2 mEq/kg NaHCO₃ administered intravenously over 30 minutes. C, Electrocardiogram of a dog with serum K⁺ concentration of 9.6 mEq/L before treatment. Note tall, tented T waves and absence of P waves. D, Electrocardiogram of the same dog 15 minutes after infusion of NaHCO₃.

(Parts C and D from Chew DJ, DiBartola SP. Manual of small animal nephrology and urology. New York: Churchill Livingstone, 1986: 132.)

The effects of hyperkalemia on the electrocardiogram have been studied in dogs and cats.^{41,43,186,187} Increased amplitude and narrowing or “tenting” of the T waves may occur with mild increases in serum potassium concentration, but these changes are inconsistent in dogs and cats. Shortening of the QT–interval may also be observed. These changes reflect abnormally rapid repolarization. Moderate hyperkalemia may result in prolongation of the PR–interval and widening of the QRS complex because of slowing of conduction through the atrioventricular system. With progression of hyperkalemia, conduction through the atrial muscle is impaired, and decreases in the amplitude and widening of the P wave are observed. In severe hyperkalemia, atrial conduction ceases, the P waves disappear, and pronounced bradycardia with a sinoventricular rhythm may be observed. In extreme hyperkalemia, the QRS complex may merge with the T wave, creating a sine wave appearance, followed by ventricular fibrillation or ventricular asystole. During progressive hyperkalemia, atrial inexcitability, depressed conduction through the specialized tissues and ventricular muscle, and the potential for reentry lead to axis deviations, widening of the QRS complex, and ventricular asystole or ventricular fibrillation. Ventricular fibrillation in hyperkalemia is most likely the result of slow intraventricular conduction and decreased duration of the refractory period. These electrocardiographic changes have also been described in cats with hyperkalemia secondary to urethral obstruction, and they represent the most life-threatening functional consequences of hyperkalemia.¹⁴⁶ Rarely, wide-complex tachycardia without identifiable P waves may occur in cats with hyperkalemia.¹⁴¹ The causes of hyperkalemia are listed in Box 5-2, and the clinical approach to hyperkalemia is presented in Figure 5-13.

Figure 5-13 Algorithm for the clinical approach to hyperkalemia.

(Drawing by Tim Vojt.)

Specific causes of hyperkalemia in dogs and cats

Increased intake of potassium is unlikely to cause sustained hyperkalemia unless impaired renal excretion of potassium is present. Exceptions include iatrogenic hyperkalemia resulting from calculation errors during continuous infusion of potassium-containing fluids or administration of drugs known to predispose to hyperkalemia with concurrent potassium supplementation. Examples of the latter situation include concurrent use of nonspecific β-blockers (e.g., propranolol) or angiotensin-converting enzyme inhibitors (e.g., enalapril) with potassium supplementation (KCl used as a salt substitute contains 13.4 mEq potassium/g) during treatment of heart failure (see Chapter 21).

Translocation of potassium from ICF to ECF can cause hyperkalemia. Acute metabolic acidosis caused by mineral acids (e.g., NH₄Cl and HCl) but not organic acids (e.g., lactic acid and ketoacids) causes potassium to shift out of cells in exchange for H⁺ ions that enter cells to be buffered. The effect of acute inorganic metabolic acidosis on serum potassium concentration in dogs is variable and was characterized by a 0.16- to 1.67-mEq/L increment in serum potassium concentration per 0.1-U decrement in pH in a review of previously published studies.⁴

Induction of hypothyroidism in beagles led to a 41% decrease in the Na⁺, K⁺-ATPase content of skeletal muscle, which was associated with a decrease in the mean resting plasma sodium concentration (from 148 to 142 mEq/L) and an increase in the mean resting plasma potassium concentration (from 3.7 to 4.3 mEq/L).¹⁷¹ Plasma potassium concentration also increased slightly after exercise in the hypothyroid dogs (up to a mean of approximately 5.0 mEq/L) but not in the euthyroid dogs presumably because decreased Na⁺, K⁺-ATPase in the hypothyroid dogs resulted in slower reuptake of potassium by muscle cells.

Insulin deficiency and hyperosmolality contribute to hyperkalemia in diabetic patients. Hyperosmolality may increase serum potassium concentration as water moves from ICF to ECF and potassium follows because of solvent drag and as a result of the increased ICF potassium concentration resulting from cellular water loss. Most diabetic patients have total body depletion of potassium caused by urinary losses, muscle mass loss, anorexia, and vomiting. A normal or low serum potassium concentration in a patient with untreated diabetic ketoacidosis indicates serious total body depletion of potassium and the need for diligent potassium supplementation. Hypokalemia at presentation is more common than hyperkalemia in diabetic dogs and cats. In one study, 43% of dogs and 83% of cats with diabetes mellitus were hypokalemic at presentation as compared with 10% of affected dogs and 8% of affected cats that were hyperkalemic.⁶⁶ Other studies of cats with diabetes mellitus have confirmed that hyperkalemia is uncommon and that 44% to 70% of affected cats had hypokalemia at presentation.^{29,44,133,173} Hypokalemia may also develop after treatment with insulin despite potassium supplementation of fluids.¹¹⁸ Consequently, the clinician must pay close attention to potassium supplementation of patients with diabetic ketoacidosis.

Massive tissue breakdown may lead to transient hyperkalemia until the kidneys excrete the released potassium. Severe exercise may cause release of potassium from cells and transient hyperkalemia in humans, and this effect is less pronounced in conditioned subjects. In untrained dogs, exercise to the point of exhaustion resulted in an increase in mean serum potassium concentration from 4.4 to 6.0 mEq/L.¹⁰⁸ Exhaustive exercise was notassociated with a significant increase in serum potassium concentration after the same dogs had been trained for 6 weeks. In racing greyhounds, no change in serum potassium concentration was observed immediately after racing, despite development of marked lactic acidosis.⁹⁸ Severe rhabdomyolysis and lethal hyperkalemia (serum potassium concentrations of 10.9 to 12.6 mEq/L) occurred in three cats with hypertrophic muscular dystrophy after restraint and anesthesia.⁷⁸ The sarcolemma of muscle cells in dystrophin-deficient animals is thought to be more sensitive to injury by anesthetic agents and intense activity resulting in release of intracellular contents. Life-threatening hyperkalemia developed in 16 of 46 (35%) cats with aortic thromboembolism treated with streptokinase because of reperfusion of ischemic muscle tissue and possibly decreased renal excretion associated with renal artery thrombosis.¹³⁴ Acute tumor lysis syndrome complicated by renal failure and hyperkalemia has been reported in dogs and cats with lymphoma treated by radiation and chemotherapy.^{34,109,110,199} There is one case report of a young pit bull dog with episodic hind limb and neck weakness. Exercise or potassium challenge resulted in mild hyperkalemia.¹⁰¹ This case may represent an example of hyperkalemic periodic paralysis. In quarter horses, hyperkalemic periodic paralysis is an autosomal dominant trait that causes recurrent episodes of muscle fasciculations and spasm.¹³¹ It is caused by a mutation in the α subunit of the sodium channel of skeletal muscle that results in impaired channel inactivation.^35,90

Decreased urinary excretion is the most important cause of hyperkalemia in small animal practice. The most common associated disorders are urethral obstruction, ruptured bladder, anuric or oliguric renal failure, and hypoadrenocorticism. The time required for development of hyperkalemia in cats after urethral obstruction is variable, but it may occur within 48 hours.^71,73 After relief of obstruction, hyperkalemia resolves within 24 hours, whereas azotemia and hyperphosphatemia require 48 to 72 hours to resolve.⁷³ After experimental bladder rupture in dogs, azotemia, hyperphosphatemia, and mild hyponatremia developed within 24 hours, whereas hyperkalemia did not develop until after 48 hours.³³ In a retrospective clinical study of uroperitoneum in cats, hyperkalemia was detected in 13 of 24 (54%) animals evaluated.¹³

In chronic renal failure, normal potassium balance is maintained, and hyperkalemia is uncommon and develops only if oliguria occurs. This renal adaptation is accomplished by increased FE_K in remnant nephrons (Fig. 5-14).^24,25,179 Fecal excretion of potassium also increases during chronic progressive renal disease and represents an extrarenal adaptation to maintain potassium balance (see Fig. 5-3). However, patients with chronic renal disease have reduced ability to tolerate an acute potassium load and may require 1 to 3 days to reestablish external potassium balance when intake of potassium is abruptly increased. Dogs with experimentally induced renal disease demonstrate decreased ability to excrete a potassium load. In the first 5 hours after a potassium load, dogs with experimentally induced renal disease excreted 30% to 37% of administered potassium, whereas control dogs excreted 56% to 67%.^24,25 Kaliuresis was blunted in the dogs with remnant kidneys despite exaggerated hyperkalemia and increased secretion of aldosterone, and approximately 24 hours were required for complete excretion of the potassium load. Episodes of moderate (>5.3 mEq/L) or severe (6.5 mEq/L) hyperkalemia occurred commonly in a population of dogs with naturally occurring chronic renal disease and responded well in 18 of 26 dogs managed by feeding them a potassium-reduced, home-prepared diet.¹⁸⁴

Figure 5-14 Nomogram relating fractional potassium excretion (FE_K) to glomerular filtration rate (GFR). Values for patients with an intact hormonal and renal tubular secretory mechanism for potassium (closed triangles) are used to delineate the hatched area. The open squares and circles indicate patients with selective aldosterone deficiency and renal tubular secretory defects, respectively.

(From Batlle DC,Arruda JA, Kurtzman NA. Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med 1981;304:373–380.)

Oliguria or anuria with hyperkalemia is more likely to occur in acute renal failure (e.g., ethylene glycol ingestion), but these findings may be observed terminally in chronic renal failure. Acute renal failure with oliguria or anuria is associated with hyperkalemia for several reasons. First, there has been insufficient time for renal adaptation to nephron loss, as occurs with chronic renal failure. Severe reductions in GFR and urine output result in inadequate distal tubular flow for effective urinary excretion of potassium. Finally, increased release of potassium from tissues during this catabolic state and acute metabolic acidosis may contribute to translocation of potassium from ICF to ECF.

Hyperkalemia, hyponatremia, and Na/K ratios less than 27:1 are usually, but not always, found in dogs and cats with hypoadrenocorticism.* In dogs with hypoadrenocorticism, hyperkalemia has been reported in 74% to 96%, hyponatremia in 56% to 100%, and Na/K ratios less than 27:1 in 85% to 100% of cases. Hyperkalemia was found in 9 of 10 cats with hypoadrenocorticism, whereas hyponatremia and Na/K ratios less than 27:1 were found in all 10 affected cats.¹⁵⁰ Treatment is begun immediately after a presumptive diagnosis of hypoadrenocorticism is made, but conclusive diagnosis requires results of an ACTH stimulation test.

If sodium intake is sufficient to maintain normal ECF volume and distal tubular flow rate, an animal with hypoadrenocorticism may be able to maintain potassium balance. Treatment of dogs with hypoadrenocorticism with fluids alone also often decreases serum potassium concentration into the normal range. However, usually these animals are presented with anorexia and vomiting that contribute to decreased ECF volume and urine output, and without adequate endogenous mineralocorticoids, they are unable to excrete sufficient potassium to prevent frank hyperkalemia.

Electrolyte abnormalities similar to those found in dogs with hypoadrenocorticism (i.e., hyponatremia and hyperkalemia) can occur in dogs with gastrointestinal disease related to trichuriasis, salmonellosis, or perforated duodenal ulcer.^53,123 Hyperkalemia in affected dogs with trichuriasis is not caused by a deficiency of aldosterone because plasma aldosterone concentrations have been found to be normal or high.⁸⁷ Hyperkalemia and hyponatremia also have been observed in dogs and cats with chylous pleural and peritoneal effusions, in a dog with pleural effusion caused by a lung lobe torsion, in a dog with a neoplastic pleural effusion, in a dog with portal hypertension and peritoneal effusion associated with Bartonella henselae infection, and in cats with peritoneal effusion caused by neoplasia or feline infectious peritonitis.^† The hyperkalemia observed in these situations is thought to arise from decreased renal excretion of potassium as a consequence of volume depletion (e.g., gastrointestinal fluid loss and third-space loss of fluid) and decreased distal renal tubular flow. Hyperkalemia and hyponatremia also have been reported in three female Greyhounds late in pregnancy.¹⁷⁵ The underlying mechanism was unknown, but all of the dogs had a history of vomiting or diarrhea. Hyporeninemic hypoaldosteronism is an important cause of unexplained asymptomatic hyperkalemia in human patients, but this disorder has rarely been recognized in veterinary medicine.⁴⁷ Many affected human patients have mild to moderate renal insufficiency caused by diabetic glomerulosclerosis or interstitial renal disease. Most of them have low plasma renin and aldosterone concentrations. Even in patients with normal plasma aldosterone concentrations, the concentration of this hormone must be considered abnormal in light of the hyperkalemia. Resting plasma cortisol concentrations and response to ACTH are normal. Hyperchloremic metabolic acidosis and hypertension may be observed. It is unclear whether low aldosterone concentrations are a consequence of diminished renin secretion and lack of trophic effect of angiotensin II on the zona glomerulosa of the adrenal cortex or whether there is a primary adrenal defect in aldosterone secretion. To document this syndrome in veterinary patients would require demonstration of subnormal plasma renin and aldosterone concentrations or a subnormal increase in aldosterone after volume contraction or ACTH administration. Normally, aldosterone concentrations increase in response to ACTH in the dog.²⁰⁷ In this study, one dog with diabetes mellitus was suspected to have hyporeninemic hypoaldosteronism based on a subnormal aldosterone response to ACTH.

Several drugs may contribute to hyperkalemia, especially when used in combination with one another, in conjunction with potassium supplementation, or in patients with renal sufficiency.¹⁴⁸ Nonspecific β-blockers (e.g., propranolol) interfere with catecholamine-mediated uptake of potassium by liver and muscle by blocking β₂-adrenergic stimulation of cell membrane Na⁺, K⁺-ATPase. Similar to digoxin, cardiac glycoside toxins found in the plant oleander (e.g., oleandrin, digitoxigenin, and Nerium) inhibit Na⁺, K⁺-ATPase and can cause hyperkalemia and arrhythmias. The deleterious effects of oleandrin are blocked by infusion of fructose-1,6-diphosphate.¹²⁶ Angiotensin-converting enzyme inhibitors (e.g., enalapril) and angiotensin II receptor blockers (e.g., losartan) contribute to hyperkalemia by decreasing production of aldosterone by the adrenal glands and blunting glomerular efferent arteriolar constriction, which potentially can decrease delivery of sodium and water to the distal nephron and impair renal potassium excretion. Prostaglandins stimulate renin release, and use of nonsteroidal anti-inflammatory drugs may contribute to development of hyperkalemia. These drugs also may impair the stimulatory effect of prostaglandins on potassium channels in the luminal membranes of renal tubular cells. Heparin impairs aldosterone production by decreasing the number and affinity of angiotensin II receptors in the zona glomerulosa of the adrenal glands and may contribute to hyperkalemia in the presence of other predisposing factors.¹⁴⁴ Potassium-sparing diuretics (e.g., spironolactone, amiloride, and triamterene) reduce urinary excretion of potassium and can cause hyperkalemia. Spironolactone competitively inhibits binding of aldosterone to its cytoplasmic receptor in the principal cells of the collecting duct. Amiloride and triamterene block sodium channels in the luminal membranes of the principal cells. Trimethoprim is similar in structure to amiloride and also inhibits sodium channels in the luminal membranes of the principal cells. Trimethoprim is most likely to cause hyperkalemia at high dosages, when urine pH is low (<6.0), and when used in patients with renal insufficiency.¹⁴⁸ The immunosuppressive drugs cyclosporin A and tacrolimus contribute to hyperkalemia in renal transplant patients by several mechanisms, including decreased aldosterone production, inhibition of Na⁺, K⁺-ATPase, and interference with luminal potassium channels in renal tubular cells. Infusions of total parenteral nutrition solutions containing lysine and arginine may contribute to hyperkalemia because these amino acids may enter cells in exchange for potassium. In many hospitalized animals, however, the cause of mild hyperkalemia cannot be determined. In these instances, hyperkalemia often resolves with appropriate fluid therapy and treatment of the primary disease.

Treatment

Appropriate treatment is dependent on the magnitude and rapidity of onset of the hyperkalemia, as well as the underlying cause. Abnormalities of serum ionized calcium concentration and acid-base balance may aggravate the functional consequences of hyperkalemia as reflected by muscular weakness and electrocardiographic changes. Thus, if compatible electrocardiographic changes are observed, hyperkalemia should be treated regardless of its magnitude. An acute increase in serum potassium concentration to more than 6.5 mEq/L should be treated promptly. Asymptomatic animals with normal urine output and chronic hyperkalemia in the range of 5.5 to 6.5 mEq/L may not require immediate treatment, but a search for the underlying cause should be initiated.

Underlying diseases should be treated promptly (e.g., relief of urethral obstruction, establishment of urine output in patients with oliguria or anuria, and 0.9% NaCl and mineralocorticoids in patients with hypoadrenocorticism). Fluid therapy with lactated Ringer’s solution (potassium concentration, 4 mEq/L) also ameliorates hyperkalemia by improving renal perfusion and enhancing urinary excretion of potassium. However, use of a potassium-free solution (e.g., 0.9% NaCl and 0.45% NaCl) has a greater dilutional effect on the ECF potassium concentration.

Hyperkalemia may be treated by antagonizing the effects of potassium on cell membranes using calcium gluconate, by driving potassium from ECF to ICF with sodium bicarbonate or glucose (with or without concurrent insulin administration), or by removing potassium from the body with a cation exchange resin or dialysis. First, any source of intake must be discontinued (e.g., potassium-containing fluids and potassium penicillin). The clinician also should review the history to verify that the patient is not currently being treated with any drug known to contribute to hyperkalemia (e.g., nonsteroidal anti-inflammatory drugs, β-blockers, angiotensin-converting enzyme inhibitors, and potassium-sparing diuretics).

Hyperkalemia decreases the resting potential of cells. By administering calcium gluconate, the ECF concentration of calcium is increased and the threshold potential is decreased, thus normalizing the difference between the resting and threshold potential and restoring normal membrane excitability (see Fig. 5-2). Administered calcium begins to work within minutes, but its effect lasts less than 1 hour. The dosage of calcium gluconate is 2 to 10 mL of a 10% solution to be administered slowly with electrocardiographic monitoring.

Glucose works by increasing endogenous insulin release and moving potassium into cells. Its effects begin within 1 hour and last a few hours. Glucose-containing fluids (5% or 10% dextrose) or 50% dextrose (1 to 2 mL/kg) can be used for this purpose. The combination of insulin with glucose may result in greater reduction in serum potassium concentration, but there is a risk of hypoglycemia.⁸ Insulin (0.55 to 1.1 U/kg regular insulin added to parenteral fluids) and dextrose (2 g dextrose per unit of insulin added) have been recommended to treat hyperkalemia in cats with urethral obstruction.¹⁷²

Sodium bicarbonate also works by moving K⁺ ions into cells as H⁺ ions leave cells to titrate administered HCO₃⁻ in the ECF. Bicarbonate begins to work within 1 hour, and its effects last a few hours. The usual dosage is 1 to 2 mEq/kg intravenously, and it can be repeated if necessary. In normal cats, 4 mEq/kg sodium bicarbonate given intravenously caused hypokalemia, hypernatremia, hyperosmolality, and decreased ionized calcium concentrations.^37,38 If a slow sinoventricular rhythm is present and caused by hyperkalemia, atropine (0.02 to 0.04 mg/kg) may increase the firing rate of the sinus node. An experimental study in dogs demonstrated no beneficial effect of alkalinization in treating hyperkalemia in anesthetized dogs. In this study, the effects of sodium bicarbonate were similar to those of hypertonic saline.¹⁰⁴ Sodium may have effects on cardiac muscle that account for reversal of hyperkalemic electrophysiologic changes.¹⁵ In a study of hyperkalemic human patients with end-stage renal disease, sodium bicarbonate alone did not decrease plasma potassium concentration, and it did not potentiate the potassium-lowering effects of insulin or albuterol.⁹

The cation exchange resin polystyrene sulfonate (Kayexalate) can be used to bind potassium and release sodium in the gastrointestinal tract. Each gram binds 1 mEq of potassium and releases 1 to 3 mEq of sodium. It can be mixed with sorbitol (to prevent constipation) and given orally or diluted in tap water and given per rectum as a retention enema using a large Foley catheter. This approach takes a few hours to work and lasts several hours. Kayexalate must be used carefully in patients with impaired ability to excrete a sodium load (e.g., those with congestive heart failure or oliguric renal failure). Intestinal necrosis also is a reported complication of polystyrene sulfonate and sorbitol given postoperatively to human patients.^81,114,185

Loop or thiazide diuretics increase the distal tubular flow rate and potassium secretion and may have adjunctive value in the treatment of hyperkalemia. The β₂ agonist albuterol increases cellular uptake of potassium by stimulating Na⁺, K⁺-ATPase activity and has been used to treat hyperkalemia in human patients with renal failure.⁷ If all of these measures fail, the clinician must consider peritoneal dialysis (see Chapter 28).⁴⁵ Hemodialysis (see Chapter 29) is more efficient at removing potassium but is available only at select referral institutions. The treatment of hyperkalemia is outlined in Box 5-3.