POTASSIUM BALANCEa

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