A P S R E F R E S H E R C O U R S E R E P O R T

PHYSIOLOGY OF K 1 BALANCE

Franklyn G. Knox

Department of Internal Medicine and Department of Physiology and Biophysics,

Mayo Foundation, Rochester, Minnesota 55905

his is an exercise involving the integration of a case presentation of diuretic-

T induced hypokalemia with the physiology of K1 balance. Students are presented

with a case presentation involving the development and correction of diuretic-
induced hypokalemia. K1 homeostasis, including the distribution of K1 in the body and
total body K1 balance, is summarized. The renal handling of K1, including the filtered
load, reabsorption by proximal segments of the nephron, and secretion by distal
segments of the nephron, is outlined. The mechanisms for the control of the secretion of
K1 are discussed. Finally, an exercise involving integration of the case presentation with
the physiology of K1 balance is presented. This exercise works well in an interactive
session with students. The exercise has proved highly useful in the presentation and
understanding of basic concepts involved in the physiology of K1 balance.
AM. J. PHYSIOL. 275 (ADV. PHYSIOL. EDUC. 20): S142–S147, 1998.

Key words: renal potassium handling; hypokalemia

An exercise concerning the physiology of K1 balance
has been used and refined as part of the first-year
curriculum in the Mayo Medical School. The exercise
incorporates three major components: a case presenta-
tion of a common clinical problem, total body K1
balance, and the renal handling of K1. The students
extract data from each of these three elements to
complete the exercise. The exercise is presented
without the answers so that the table at the conclu-
sion of the exercise can be used in an interactive
fashion with students. Student feedback on this exer-
cise has been very positive, with students comment-
ing that ‘‘working with the numbers helped with an
understanding of the concepts.’’
EXERCISE: INTEGRATION OF A CASE
PRESENTATION OF DIURETIC-INDUCED
HYPOKALEMIA WITH THE PHYSIOLOGY
OF K1 BALANCE
The objective of this exercise is to apply the basic
principles of the physiology of K1 balance to a case
presentation describing the development and correc-
tion of diuretic-induced hypokalemia.
Case presentation: Diuretic-induced hypokale-
mia. A middle-aged man who weighed 20 lb over his
ideal weight presented blood pressure elevated to
160/110 mmHg. He had no cardiovascular complica-
tions of hypertension and normal levels of serum
creatinine and K1 (4 meq/l). Hydrochlorothiazide (a
diuretic that decreases Na1 reabsorption in the distal
nephron) at 25 mg twice daily was prescribed, with
advice to return for reexamination in 1 mo.
He returned 1 mo later complaining of muscle cramps,
frequent nighttime urination, and general weakness.
His blood pressure was 150/90 mmHg, and the serum
creatinine was still normal. However, the serum K1
concentration had decreased to 3.0 meq/l. A 24-h
urine specimen contained 256 meq of Na1. Because
the urinary excretion of Na1 usually approximates the
dietary intake, it was concluded that he was ingesting
excessive Na1. A nutritionist instructed the patient in

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a 90-meq Na1 diet with weight-reduction features. both the dietary intake of K1 and its excretion from
The hydrochlorothiazide was continued, but both the body.
25-mg tablets were now to be taken in the morning,
with none being taken at bedtime. DISTRIBUTION OF K1 IN THE BODY

One month later, the patient’s blood pressure was
130/90 mmHg, he had lost 8 lb, and the serum K1
concentration was 4.0 meq/l. He was urinating only
once or twice during the night, and the cramps in his
legs were no longer troublesome.
K1 HOMEOSTASIS
K1 is the major intracellular cation (1). A high level
within cells is important for the optimal operation of
many enzymatic processes and the control of cell
volume. In addition, the establishment of a K1 concen-
tration ([K1]) difference across the plasma membrane
of the cell is important for the normal function of
excitable tissues.
Virtually all K1 within the body is contained inside
cells, with only 2% being located in the extracellular
fluid space. The distribution of K1 within the body is
summarized in Fig. 1.
In the steady state, the intake of K1 into the body must
be matched by its excretion, a process occurring
primarily via the kidneys. However, the renal re-
sponses to fluctuations in K1 intake are not immedi-
ate, and it takes several hours or even days for
appropriate adjustments in K1 excretion to occur.
Wide fluctuations in the [K1] of the extracellular fluid
are prevented during the ‘‘lag period’’ by shifts of K1
between the intracellular extracellular compartments
(extrarenal K1 homeostasis).

The extracellular fluid [K1] is a function of the total The extrarenal handling of K1 is essential for the
body K1 content and the relative distribution of K1 maintenance of plasma [K1] within a narrow range.
between the extracellular and intracellular fluid com- This is especially true during situations in which the
partments. The total body K1 content depends on body is challenged with an acute load of K1. Thus,

FIG. 1.
Overview of K1 homeostasis. An increase in plasma insulin, epinephrine,
and aldosterone stimulates K1 movement into cells and decreases plasma
K1 concentration ([K1]), whereas a decrease in plasma concentration of
these hormones increases plasma [K1]. The amount of K1 in the body is
determined by the kidneys. An individual is in K1 balance when dietary
intake and urinary output (plus output by the gastrointestinal tract) are
equal. Excretion of K1 by kidneys is regulated by plasma [K1], aldoste-
rone, and antidiuretic hormone.

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with an acute K1 load (dietary or otherwise), K1 is

rapidly taken up into cells (liver, skeletal muscle,
adipose tissue). This prevents a large rise in plasma
[K1]. Over the next several hours K1 is slowly
released from these storage sites and excreted by the
kidneys.

With potassium depletion, which occurs with diuretic

therapy, the losses from the extracellular fluid are not
fully compensated for by shifts from the tissue stores.
A decrease in the plasma K1 from 4 to 3 meq/l
corresponds to an ,300-meq K1 deficit as determined
empirically (Fig. 2) (2). Note that if the loss of K1 from
the plasma were proportionate to the loss of total
body K1, it would equal a total body K1 deficit of
1,000 meq.
FIG. 3.
K1 transport along nephron. K1 excretion depends on rate
RENAL K1 EXCRETION
and direction of K1 transport by distal tubule (DT) and
The kidney can vary the amount of K1 excreted in the cortical collecting duct (CCD). Percentages refer to amount
of filtered K1 reabsorbed or secreted. Normal and increased
urine over a wide range. The kidney is able to excrete
dietary K1 intake. An amount of K1 equal to 15–90% of
large amounts of K1. Accordingly, with normal renal filtered load is excreted. PT, proximal tubule; TAL, thick
function and even in the face of a large dietary K1 ascending limb.
intake, significant hyperkalemia is rarely seen. In
contrast, the kidney is less well able to conserve K1 convoluted tubule and the cortical portion of the
(fractional K1 excretion can be reduced to ,2% of the collecting duct. These general aspects of renal K1
filtered load). Thus K1 depletion and hypokalemia can handling are summarized in Fig. 3.
result if K1 intake is restricted.
Note that ,90% of the filtered load of K1 is reab-
The process of renal K1 excretion involves two sorbed before the K1 secretory site. The amount of K1
general steps. First, 90% of the filtered load of K1 is appearing in the urine reflects in large part the
reabsorbed. This occurs in the proximal tubule and secretion of K1 at the distal secretory sites. Several
the loop of Henle. Second, K1 is secreted into the factors have been identified as important regulators of
tubular fluid by the terminal portion of the distal K1 secretion and will be considered in detail below.

REABSORPTION OF FILTERED K1

Glomerulus. K1 is a small cation and is not bound in

any appreciable amount to plasma protein. As a result,
the K1 in the glomerular filtrate is essentially the same
as in the plasma water. The filtered load of K1 is then
plasma [K1] (4.0 meq/l) multiplied by the glomerular
filtration rate (180 l/day), or 720 meq/day.

Proximal tubule. The proximal tubule (convoluted

and straight) reabsorbs roughly 80% of the filtered
load of K1. This fraction remains relatively constant
FIG. 2.
under most conditions. Thus the proximal tubule does
Effect of K1 depletion on plasma K1 concentration [adapted not normally contribute significantly to the regulation
from Sterns et al. (2)]. of urinary K1 excretion.

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The reabsorption of K1 by the proximal tubule
probably involves both passive and active mecha-
nisms. Under most conditions, K1 reabsorption is
proportional to the amount of NaCl and fluid reab-
sorbed.
Loop of Henle. Approximately 10% of the filtered
load of K1 is reabsorbed by the thick ascending limb
of Henle’s loop. Under normal conditions, the reab-
sorption of K1 is relatively constant, although this
segment does have the capacity to increase K1 absorp-
tion in response to an increased load.
SECRETION OF K1
Distal tubule and collecting duct. It is the distal
convoluted tubule and the cortical portion of the
collecting duct that primarily determine the amount
of K1 appearing in the urine. The more terminal
portions of the collecting duct can affect minor
adjustments in urinary K1 excretion.
Under most conditions (normal western diet), K1 is
secreted at these sites. However, with K1 depletion,
reabsorption of K1 occurs. These two transport mecha-
nisms are located in separate cells. The secretory cell
is the ‘‘principal cell,’’ whereas the ‘‘intercalated cell’’
is the cell responsible for K1 reabsorption.
K1 secretion occurs by a two-step process. First, K1 is
brought into the cell across the basolateral cell mem-
brane (Na1-K1-ATPase). Some K1 recycles across this
membrane, but a portion enters the tubule lumen by
passive diffusion across the apical cell membrane. The
amount of K1 that either recycles back to the blood
across the basolateral cell membrane or enters the
tubule lumen is determined by the permeability of
each membrane to K1 and the respective electrochemi-
cal gradients for K1. Normally, the apical cell mem-
brane is more permeable to K1. In addition, as shown
in Fig. 4, the electrical profile across the cell favors
luminal K1 entry.
REGULATION OF K1 EXCRETION
To understand the regulation of renal K1 excretion, it
is important to focus on the secretion of K1 by the
terminal portion of the distal convoluted tubule and
the cortical portion of the collecting duct (K1 secre-
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FIG. 4.
Cellular mechanism of K1 secretion by principal cell in distal
tubule and collecting duct.
tory site). Several factors act at this site to regulate K1
secretion and thereby K1 excretion.
Dietary K1. Urinary K1 excretion parallels dietary
intake. With dietary K1 loading, K1 secretion is
enhanced. This is the result of increased uptake of K1
into cells (via Na1-K1-ATPase) and is largely the result
of changes in mineralocorticoid hormone levels (see
Hormones). Conversely, cellular uptake of K1 is
reduced with K1 depletion, again in response to
changes in mineralocorticoid hormone levels.
Plasma K1. As plasma K1 is increased, K1 secretion
also increases, reaching a plateau at a plasma [K1] of
,6 meq/l. Because increases in plasma [K1] stimulate
aldosterone secretion, the increased K1 secretion can
be attributed in part to mineralocorticoid-induced
uptake of K1 into the K1 secretory cells. In addition,
elevated plasma [K1] would also be expected to
reduce the passive component of K1 recycling across
the basolateral cell membrane. Together, these effects
increase K1 excretion.
Hormones. The most important hormone regulating
K1 secretion by the terminal portion of the distal
convoluted tubule and the cortical portion of the
collecting duct is aldosterone. Aldosterone stimulates
K1 secretion by increasing cellular uptake of K1 via
the Na1-K1-ATPase and by increasing the K1 permeabil-
ity of the apical cell membrane of the K1 secretory
 A P S R E F R E S H E R C O U R S E R E P O R T

cells. Aldosterone also stimulates Na1 reabsorption by TABLE 2

these nephron segments. This, in turn, increases the Integration of the case presentation with the physiology of
K1 balance: Answers to the exercise
transepithelial potential difference and further stimu-
lates K1 secretion. Initial 1-Mo Visit 2-Mo Visit
Presentation (High-Na1 (Low-Na1
K1
Luminal flow rate. As the flow of tubular fluid past (High-Na1 diet1 diet1
the K1 secretory site is increased, K1 secretion is diet) diuretic) diuretic)
increased. This flow-related increase in K1 secretion is Intake, meq/day 100 100 100
thought to result from the maintenance of a favorable
cell-to-lumen concentration gradient for K1. Because Plasma, meq/l 4.0 3.0 4.0
the amount of K1 secreted into the tubule lumen will Total body, meq 3500 3200 3500
be limited by this gradient, a fast flow rate (decreased
contact time) will prevent luminal K1 from rising to Excretion, meq/day 90 100 80
levels that would subsequently limit further K1 secre- Filtered, meq/day 720 540 720
tion.
Reabsorbed, meq/day 648 486 648
EFFECTS OF DIURETICS ON K1 EXCRETION Distal delivery (Filt-Reab), 72 54 72
meq/day
Diuretics commonly increase renal K1
excretion.
Those diuretics that have their site of action proximal Distal secretion (Exc-Del), 18 46 8
to the K1 secretory site will increase urinary K1 loss meq/day
(e.g., osmotic diuretics, carbonic anhydrase inhibi-
tors, loop diuretics, and thiazides). The increased K1 the loop diuretics inhibit K1 reabsorption by the thick
secretion results from the diuretic-induced increase in ascending limb. The K1-sparing diuretics (spironolac-
luminal fluid flow rate and delivery of Na1. In addition, tone, triamterene, and amiloride) prevent K1 loss in
the urine through inhibition of its secretion.
TABLE 1
Integration of the case presentation with the physiology
From the case presentation and the syllabus materials,
of K1 balance: exercise
complete the distribution of K1 and the renal handling
Initial 1-Mo Visit 2-Mo Visit of K1 for the patient’s initial presentation and at the 1-
Presentation (High-Na1 (Low-Na1 and 2-mo visits (Table 1). The answers to the exercise
K1
(High-Na1 diet1 diet1 are found in Table 2.
diet) diuretic) diuretic)

Intake, meq/day DISCUSSION

Plasma, meq/l At the initial presentation, the dietary intake of K1 is

100 meq of K1 per day as derived from Fig. 1. The
Total body, meq excretion of K1 is 90 meq/day, also as derived from
Excretion, meq/day 1 2 Fig. 1. The plasma K1 is 4 meq/l as derived from both
the case presentation and the syllabus. The total body
Filtered, meq/day K1 is 3,500 meq as derived from the information in
Reabsorbed, meq/day Fig. 1, including both tissue stores and extracellular
fluid. The filtered K1 is 720 meq/day (as derived from
Distal delivery (Filt-Reab), the syllabus), where the filtered load is equal to 4
meq/day
meq/l 3 180 l/day. The reabsorbed K1 is equal to 90%
Distal secretion (Exc-Del), of the filtered load shown in Fig. 3. The distal delivery
meq/day is simply the filtered minus reabsorbed K1 at 72
1Calculate average daily K1 excretion to account for the decrease in
meq/day. The distal secretion, therefore, is the ex-
total body K1. 2Calculate average daily K1 excretion to account for creted K1 (90 meq/day) minus the delivered K1 (72
the increase in total body K1. meq/day), which is 18 meq/day.

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At the 1-mo visit, the K1 intake continues at 100
meq/day. The excretion can be calculated from the
K1 loss. The plasma K1 concentration is 3 meq/l as
obtained from the case presentation. This results from
a decrease in total body K1 of 300 meq as obtained
from the information in Fig. 2. A 300-meq loss over a
30-day period represents a 10 meq/day increase in K1
excretion over the initial 90 meq/day. Thus the K1
excretion at the 1-mo visit has averaged 100 meq/day.
The filtered K1 is now 540 meq/day, and the reab-
sorbed K1 is 486 meq/day. The distal delivery is 54
meq/day, and, because the excretion is 100 meq/day,
the distal secretion is 46 meq/day.
At 2 mo, this process is reversed. The K1 intake
remains 100 meq/day, the excretion is calculated to
be 80 meq/day, and the distal secretion now becomes
8 meq/day. Thus this exercise described the major
role of distal secretion in determining final urinary
excretion. In addition, it shows the marked effect of
changes in Na1 intake on the renal handling of K1 in
diuretic therapy. The high Na1 intake leads to in-
creased delivery of Na1 and water to the distal
nephron, where the luminal flow rate is further
increased by the diuretic and leads to increased K1
secretion. The low Na1 intake reduces the delivery of
Na1 and water to the distal nephron so that the effect
of the diuretic on K1 secretion is offset and K1 balance
is restored.
The case presentation is taken from an actual clinical
case. However, the presentation has been simplified
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C O U R S E R E P O R T
by having the low-Na1 diet completely correct the
hypokalemia. In the original case, the low-Na1 diet
partially corrected the hypokalemia with a final serum
K1 concentration of 3.5 meq/l. The simplification
allows for a symmetrical calculation of the changes in
distal K1 secretion. The exercise, of course, can be
performed with the incomplete correction of the
hypokalemia; however, this tends to complicate the
calculations and interfere with the presentation of the
basic principles.
A second simplification involves the attribution of the
entire correction of the hypokalemia to changes in
distal K1 secretion. In the presence of K1 conserva-
tion, reabsorption of K1 may also occur in the distal
nephron segments. These two points can be brought
out in the context of the discussion of Table 2 at the
conclusion of the exercise. The exercise has been
found to be useful in presenting and utilizing basic
concepts involved in the physiology of K1 balance.
Address reprint requests to the author.
References
1. Koeppen, B. M., and B. A. Stanton. Regulation of renal
physiology. In: Renal Physiology (2nd ed.). St. Louis, MO:
Mosby Year Book, 1997, chapt. 7, p. 117–133.
2. Sterns, R. H., M. Cox, P. U. Feig, and I. Singer. Internal
potassium balance and the control of plasma potassium concen-
tration. Medicine 60: 339–354, 1981.