POTASSIUM BALANCE

Dr. T. Dixon

 

Objectives

 

-To understand the mechanisms responsible for the maintenance of potassium homeostasis, its distribution between intra- and extra-cellular compartments.

            -To learn about hormonal regulation of potassium homeostasis.

            -To obtain a clear picture on the role of the nephron in maintaining potassium homeostasis

            -To understand urinary tests designed to diagnose the disorderes of potassium homeostasis.

            -To enable the diagnosis of causes of hypokalemia.

            -To enable the dignostic workup of a patient with hyperkalemia and provide a pathophysiologically relevant therapy of this condition.

 

           

            External and internal potassium balances are regulated to maintain an extracellular fluid (ECF) concentration of 3.5 to 5.5 mEq/L and a total body content of about 50 mEq/Kg (40 mEq/kg in females).  A simplified daily balance sheet would show the following:

 

Input

Output

Dietary K+ 50-125 mEq

Urine 45-112 mEq

 

Feces 5-12 mEq

 

 

 

            A more detailed example that accounts for the distribution of potassium within the body is given in the following figure.

            Balance usually is disrupted by increase in renal, gastrointestinal, or skin losses which produce negative balance; or decreases in renal excretion which produces a positive balance.  Changes in body potassium content (>95% in cells) are not necessarily reflected in plasma potassium concentration.  Therefore, it is necessary to examine factors that regulate internal balance by regulating the distribution of potassium between the intracellular and extracellular fluids.

 

 

            1.  Factors Regulating Plasma Potassium (Internal Balance)

a.  Blood pH

            Academia causes a shift of K+ from the intracellular space of cells into the plasma; whereas, alkalemia causes a shift of K+ from the plasma into cells.  These shifts result in a change in internal potassium balance.  A very rough guide of the magnitude of this redistribution of potassium is that plasma K+ may rise about 0.6 mEq/L for each decrease in pH of 0.1 units.

            This redistribution of potassium is not solely dependent on the acidity since different types of acids result in different magnitudes of potassium shifts.  Mineral acidosis (where the anion associated with the acidosis is chloride, sulfate or phosphates) are usually associated with the degree of shift described above.  On the other hand, shifts in the distribution of potassium usually do not result from acidosis caused by nonmineral or organic acidosis (where the accompanying anion is lactate, acetate, beta-hydroxybutyrate etc.).

            The plasma bicarbonate concentration seems to have an effect on the uptake of potassium by cells that is independent of the pH of the blood.  Under conditions of constant blood pH, infusion of sodium bicarbonate leads to a decrease in plasma potassium concentration.

b.  Insulin

            Insulin is the first-line defense against hyperkalemia.  A rise in plasma K+ stimulates insulin release by the pancreatic beta cell.  Insulin, in turn, enhances cellular potassium uptake, returning plasma K+ towards normal.  The enhanced cellular uptake of K+ that results from increased insulin levels is thought to be largely due to the ability of insulin to stimulate activity of the sodium potassium ATPase located in cell plasma membranes.  The insulin induced cellular uptake of potassium is not dependent on the uptake of glucose caused by insulin.  Insulin deficiency allows a mild rise in plasma K+ chronically and makes the subject liabel to severe hyperkalemia if a potassium load is given.  Conversely, potassium deficiency may cause decreased insulin release.  Thus plasma potassium and insulin participate in a feedback control mechanism.

c.  Catecholamines

            Catecholamines are also involved in the regulation of the distribution of potassium as described in the following table.  Notice that beta-2-agonists lower plasma potassium (by causing a cellular uptake of potassium) and alpha agonists increase plasma potassium concentration..

 

d.  Physical Conditioning and Exercise

            Strenuous exertion may injure muscle cells and allow leakage of K+ into the ECF.  Highly trained athletes may have normal total body K+ content, but redistributed K+ into muscles, thus producing hypokalemia.

e.  Activity of Cell Membrane Na-K ATPase

            These ion pumps use ATP to fuel transport of sodium from the cell to the ECF in exchange for the uptake of potassium by the cell, and thus are an important menas of regulating the distribution of potassium between intra and extracellular compartments.  Some of the other regulators of internal potassium balance such as insulin, physical training, catecholamines may exert their effect by altering the activity of the sodium potassium ATPase in cell membranes.

2.  Factors Regulating Body Potassium Content (External Balance)

a.  Renal Excretion of K+

            The Kidney can rapidly excrete large loads of potassium, 200-300 mEq/day, with out a change in plasma K+ or body K+ content.  Potassium is filtered freely at the gomerulus but 90-95% is reabsorbed in the proximal tubule.  The major site of renal regulation of potassium excretion occurs in the distal tubules and collecting ducts where variations in the amount of potassium absorbed from or secreted into the urine regulates potassium balance.  In contrast to the ability to increase excretion rapidly to meet increased input, the ability to reduce excretion to zero or very low levels is slow, taking perhaps 2 to 4 weeks.  Thus, negative external balance due to sudden decreased in K+ intake or increases in gastrointestinal or skin losses will be furthered by a continued leak of K+ into the urine until the condition is chronic.  The major determinants of urinary potassium excretion include the following:

            1)  Aldosterone

            Aldosterone stimulates distal nephron secretion of potassium.  The stimulation of secretion is related to the ability of aldosterone to stimulate sodium potassium ATPase activity in cells of the distal tubule as well as its ability to alter the apical (urinary) membrane conductance of potassium in these cells.  In the absence of aldosterone, body potassium content and plasma K+ are increased due to a decrease in renal excretion of potassium.  In the presence of excess aldosterone both total body K+ and plasma K+ are decreased.  An increased plasma K+ stimulates aldosterone secretion and decreased plasma K+ suppressed it.

            2)  Urine Flow Rate

            Increase urinary flow rate increases urinary potassium excretion, presumable by maintaining chemical gradient for potassium that favor the passive secretion of potassium from the cell into the urinary filtration cells of the distal tubule.

            3)  Urinary Sodum Concentration

            Sodium delivery to distal nephron may promote K+ excretion (Na-K exchange), but it is not certain if this is independent of flow rate since in most instances increased urinary sodium is accompanied by increased urinary flow rate.

            4)  Non Reabsorbable Anions (Urinary Cl- Concentration)

            Sulfates and others create favorable electrical (lumen negative) gradients for passive secretion of potassium into the urine.  Additionally, the decreased urinary chloride concentrations present under these circumstances contribute to potassium excretion by inhibiting the reabsorption of potassium by the K-H ATPase present in intercalated cells of the distal tubule.

            5)  Plasma K+ Concentration

            Changes in the peritubular plasma K+ concentration lead to changes in the rate of secretion of potassium by distal tubular cells.  Increased plasma K+ leads to an increased rate of secretion presumably due to an increased cellular K+ concentration that creates a more favorable gradient for the passive secretion of K+ into the urine.  Decreased plasma K+ has the opposite effect.

            6)  pH of the Blood

            Acutely alkalosis leads to an increase in the K+ concentration of the cells of the distal tubule, this leads to a more favorable gradient that is associated with increased urinary secretion of potassium.  Acidosis has the opposite effect.  With chronic changes in acid-base status, the relationship between changes in pH of the blood and potassium excretion are more complex and the relationship found in the actute state may be altered.

b.  Gastrointestinal Potassium Excretion

            Normally 10 – 15% of K+ intake is excreted by the gut.  Aldosterone is one of the regulators of secretion of potassium by the gastrointestinal tract.  Diarrhea increased fecal K+ losses, particularly laxative-related diarrhea.  Diarrhea may contain 100 mEq/L of K+.

c.  Skin Potassium Excretion

            Normally only a trivial amount of K+ is excreted in perspiration.  However, working in hot temperatures may produce up to 10-12 liters of sweat per day containing 10 mEq/L of K+.  Thus major K+ losses may occur via this route.  Of interest, sweat K+ is also under control of the hormone aldosterone.

3)  POTASSIUM ADAPTATION

            If an experimental animal is maintained on a low or moderate potassium intake, a sudden increase in dietary potassium, may result in severe hyperkalemia and the animal may die.  However, if the low potassium diet is gradually supplemented with additional potassium the same large potassium loads which previously had produced dangerously high plasma potassium levels become harmless.  The animal has become adapted to high potassium loads through the process of ingesting gradually increasing amounts of potassium in its diet.  The physiologic components of the adaptation include the ability to excrete a potassium load more quickly (renal potassium secretory rates are markedly enhanced) and the temporary storage potassium in the intracellular fluid is more effective.  Thus, following a large load of potassium, plasma potassium levels do not rise to the same degree in the potassium adapted animal as they do in the nonadapted animal

            The mechanism(s) responsible for potassium adaptation are not well understood.  There is evidence that diets high in potassium result in increased aldosterone secretion rates, increased insulin release, the induction of larger amounts of Na K ATPase in the cells of the renal tubule and the large intestine.  It can be shown that the potassium secretory capacity of the distal nephron (specifically the distal half of the distal convoluted tubule and the cortical collecting tubule) is markedly enhanced in animals on high potassium intake and this enhancement can be shown to characterize the function of the isolated nephron segment in vitro as well as in vivo.

HYPOKALEMIA

            Hypolkalemia usually but not always is a sign of potassium deficiency.  Internal shifts due to pH and other factors must be considered in evaluating the change in potassium content.  A rough guide for the evaluation of K+ deficiency displayed in the following figure which depicts total body potassium deficiency as a function of serum potassium.  Notice the variability in the amount of total body K+ deficiency present for a given serum K+ concentration.

Figure 2. Relationship of serum potassium concentration to body potassium deficit . The data are derived from seven metabolic balance studies out on 24 subjects depleted of potassium. (From RH Sterns et al. Medicine 60:339,1981)

1.  Consequences of Hypokalemia/Potassium Deficiency

a.  Metabolic Effects

            Hypokalemia suppresses insulin release leading to glucose intolerance.  Potassium deficiency in children retards growth.

Hypokalemia causes intracellular acidosis and increased renal ammonia production.  In the patients with encephalopathy due to cirrhosis of the liver, hypokalemia may worsen the encephalopathy.

b.  Cardiovascular Effects

            Hypokalemia causes electrophysiologic abnormalities that result in changes in the EKG depicted in the follow figure.

Figure 3. The EKG abnormalities associated with hypokaliemia include the following:

         -decreases amplitude or inversion of the T wave

-          increases amplitude of the U wave

-          prolongation of the Q-U interval

-          Increased amplitude of the P wave, prolongation of the P-R interval

-          Wideving of the QRS complex

Hypokalemia enhances the development of atrial and ventricular arrhythmias in patients on digits.

c.  Neuromuscular Effects

            Hypokalemia causes muscle weakness, even paralysis.  Muscle membranes may be injured producing rhabdomyolysis.  Ileus of the gut may also occur.

The neuromuscular and cardiovascular effects can partically be predicted based on the electrophysiology depicted in the figure below.  Changes in potassium exert their effect by altering resulting membrane potential.  This, as we shall see, can be used to formulate therapy in hyperkalemia with calcium which alters threshold potential.

 


           

d.  Renal Effects

            Hypokalemia causes both increased thirst and a renal concentrating defect resulting in polyuria.  Prolonged hypokalemia causes proteinuria, proximal renal tubule vaculization, interstitial fibrosis and possibly decreased renal blood flow and glomerular filtration rate.  Hypokalemia stimulates acid secretion by the kidney as well as production of the urinary buffer ammonia thus potentially causing alkalinization of the blood.

2.  Causes of Hypokalemia/Potassium Deficiency

            The lack of a fixed relationship between plasma K+ concentration and body K+ content allows three groups of disorders.

            a.  Hypokalemia without potassium deficit

            b.  Hypokalemia with potassium deficit

            c.  Potassium deficit without hypokalemia

            The table provides a comprehensive list of causes.  This list is mildly overwhelming.  In order to sort through this list, use the balance concept.  This will allow you to ask five basic questions.  (Also, note the three * categories account for greater than 90% of cases).

Hypokalemia without potassium deficit

            Respiratory alkalosis

            Familial hypokalemic periodic paralysis

            Athletes

Hypokalemia with potassium deficit

Poor dietary intake

            Tea and toast diet

            Alcoholism

            Anorexia nervosa

            Geophagia

Cellular incorporation

            Treatment of megaloblastic anemia

            Intravenous hyperalimentation

Gastrointestinal loss

* Protracted vomiting

* Diarrhea

            Laxative abuse

            Ureterosigmoidoscopy

            Obstructed or long ileal loop

            Villous edema

Urinary Loss

Excess mineralocorticoid effect

            Primary or secondary hyperaldosteronism

            Bartter’s syndrome

            Excessive glucocorticoid hormones (Cushing’s syndrome)

            Licorice abuse

            Excessive ACTH

            Renal tubular acidosis

            Endogenous or exogenous osmotic diuretic

            * Diuretic therapy

            Carbenicillin, penicillin therapy

            Leukemias

Potassium deficit without hypokalemia

            Acid-base disturbance

            Uremia

            Congestive heart failure

Approach to the hypokalemia patient:

1)  Is there an internal shift of potassium?

            Look for alkalemia, excessive insulin activity (glucose or, insulin infusion), excessive beta agonist activity (isoproterenol administration), unusual disorders such as periodic paralysis (thyrotoxicosis).

2)  Is there excessive gastrointestinal loss of potassium?

            Look for diarrhea, vomiting, laxative use.

3)  Is there excessive renal loss of potassium?

            Look for diuretic use and the more uncommon things listed in the table.

4)  Is there excessive sweating?

5)  Is there a very low potassium intake?

            Another approach is to think of the renal response to a potassium deficit (slow decrease in K+ excretion) and the effect of acid-base disorders on K+ (internal shifts, renal K+ losses with metabolic alkalosis).  Thus excessive lower gastrointestinal K+ losses leading to chronic hypokalemia should cause renal K+ excretion to fall.

3.  Treatment of Hypokalemia/Potassium Deficiency

            The goal of treatment is to restore plasma and total body K+ to normal.  In an emergency such as a cardiac arrhythmia or paralysis, potassium must be given intravenously with caution.  Generally oral supplements are preferable when feasible.  Supplementation of the diet with potassium rich foods should also be done when feasible.  Diuretics that reduce renal K+ excretion may be useful at times (spironolactone, trimterene, amiloride) depending on the clinical situation.

HYPERKALEMIA

            Hyperkalemia is less common than hypokalemia but may be more dangerous.  Plasma (or serum) levels above 7.0 mmol/L seriously derang organ function and levels above 8-10 mmol/L are often fatal.

1.  Consequence of Hyperkalemia

            a.  Cardiac Effects

            An acute rise in plasma K+ reduces the ratio of Ki/Ko which raises cell membrane potential toward the threshold potential.  The ECG effects of hyperkalemia are demonstrated in the following figure.

 

Figure 5. EKG changes associated with hyperkaliemia:

-          ca. 6 mEq/l increased amplitude of T wave with shortened Q-T interval

-          ca. 7-8 mEq/l widening of QRS complex, decreased amplitude of P wave with eventunal loss of P wave

-          following these changes ventricular fibrillation, cardiac standstill

            b.  Neuromuscular Effects

            These resemble the changes in hypokalemia but are due to depolarization, not hyperpolarization.  Thus weakness progressing to paralysis may occur.

 

2.  Causes of Hyperkalemia

Pseudohyperkalemia

     Tourniquet method of drawing blood

     Hemolysis of drawn blood

     Increased WBC or platelet count (­­­)

The table contains a detailed listing of the causes of hyperkalemia.  Of note is the occurrence of pseudohyperkalemia.  Use of a syringe with heparin as the anticoagulant and avoidance of a tourniquet will avoid the generation of a technical elevation of potassium concentration.  Again the use of the balance will allow rational analysis.
 
True hyperkalemia

     Redistribution

        Acidosis

        Hyperkalemic familial periodic paralysis

        Digitalis intoxication

        Beta adrenergic blockade 

Decreased excretion

        Chronic or acute renal failure

        Hyporeninemic hypoaldosteronism

            Selective renal impairment of potassium excretion

        Systemic lupus erthematosis

        Renal allograft

        Sickle cell disease

Increased input      

Endogenous input

        Hemolysis

        Rhabdomyolysis

     Exogenous input

        Salt substitutes

        Potassium penicillin

 

Approach to the hyperkalemic patient:

1)   Is this true hyperkalemia?

2)  Is there an internal shift of K+ into the ECF?

     Look for academia, massive digits intoxication , adrenergic blockade, tissue injury.

3)  Is there decreased renal potassium excretion?

     Look for severe renal failure (GFR below 10 ml/min), hypoaldosteronism, K+, sparing diuretics.

4)  Is there a major increase in K+ input?

     Look for IV infusion faster than 40 mEq/h, dietary intake greater than 300 mEq.  If renal failure is present, look for use of “salt substitute” which KCl.

3.  Treatment of Hyperkalemia

     Treatment of serious hyperkalemia is based on reversing physiological problems.  The following table describes the principles and types of treatment.

Principal

Treatment

Onset

Duration

Reversible Depolarization

Calcium infusion

1-3 minutes

30-60 minutes

Shift K+ into cells

Insulin

15-30 minutes

12-24 hours

 

NaHCO3 infusion

15-60 minutes

12-24 hours

 

Beta agonst

30 minutes

2-4 hours

Remove K+ from body

Kayexelate

1-2 hours

4-6 hours

 

(Ion exchange resin by mouth)

 

 

 

Diuretics (furosemide)

Start of Diuresis

End of Diuresis

 

Hemodialysis

Rapid

Duration of dialysis