GASTROENTEROLOGY 1994;107:949-571

SPECIAL REPORTS AND REVIEWS

Pathophysiology of Potassium Absorption and Secretion by

the Human Intestine

RAJIV AGARWAL, REKHA AFZALPURKAR, and JOHN S. FORDTRAN

Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas

T he renal transport of potassium has been extensively key. Processed foods generally contain higher Na+ and
reviewed and analyzed on a number of occasions, but lower Kf than fresh foods. The increased requirements
there has been no similar in-depth treatment of intestinal during lactation (maternal milk contains 12.8 mEq/L),
absorption. In this review, we have attempted to eluci- fetal growth, and infancy are easily supplied by usual
date the role of intestinal absorption in K+ homeostasis intakes of Kf.6
under normal conditions and when physiology is de- The normal K+ intake values quoted in the previous
ranged by disease. Because absorption is determined by paragraph are in reference to people living in the United
dietary K+ intake and intestinal K+ transport processes, States. In some cultures, people ingest much more K+
both diet and intestinal transport physiology are ana- in their diet. For example, the cooking banana Mtisa
lyzed. Particular emphasis is placed on the physiological paradisca is the major food source of the Yanomama Indi-
factors that regulate K” transport, the factors that deter- ans, a tribe of tropical forest Indians living near the
mine K+ losses in diarrhea1 disease, and the degree to border of Venezuela and Brazil. Judging from urinary
which the intestine can adapt its absorption and secretion Kt excretion, the dietary Kf intake of adult men must
of K+ in response to extraintestinal disease. Much of be at least 300 mEq/day; because average body weight
the data we describe was reported many years ago when is only 54.9 kg, dietary K+ intake probably exceeds 5.5
metabolic balance studies were in vogue; however, for mEq/kg. The dietary Naf intake of these men is probably
the most part, this body of knowledge has not previously < 10 mEq/day, and they have very high levels of serum
been used for the present purpose. and urinary aldosterone. At least where Na+ intake is
This review is almost entirely confined to studies in the extremely low, people can live in good health on a diet
human intestine in vivo; those interested in the cellular containing enormous amounts of K+ by United States
mechanisms of K+ transport are referred to reviews re- standards.’
ported elsewhere.’
Metabolic Balance Studies in Normal
Normal Kf Balance Subjects
Body Stores Only a few metabolic balance studies of Kf have
Kf is the major intracellular cation. Total body been conducted, and most of these were reported more
“exchangeable” K+, measured with the use of radioactive than 40 years ago. The studies were usually not per-
42K, averages 46 mEq/kg in men and 39 mEq/kg in formed to define normal K+ balance, but sometimes this
women.2,3 Only 1.5%-2.5% of total body Kf (about 65 information becomes available from the control periods
mEq) is found in the extracellular fluid. of experiments designed for other purposes.
Normal balance. K+ balance in normal subjects
Normal Dietary K+ Intake
during ingestion of a normal diet was studied by Deitrick
Normal teenage boys and adult men ingest about et al., whose primary interest was the metabolic response
78 mEq/day of K+ in their diet*; on average, men ingest to immobilization.8 The control period of normal activity
more K+ than women.5 Vegetables, fruits, meats, and lasted 6-7 weeks. Four normal subjects were studied.
dairy products are the main sources of dietary K+ in Their average K+ intake was 92.5 mEq/day (range, 81-
normal healthy adult Americans. Although each food 96 mEq/day), average fecal K+ output was 9.8 mEq/day
group may contain foods rich or poor in K+, some of the
foods particularly rich in K+ are potatoes, beans, bananas, 0 1994 by the American Gastroenterological Association
oranges, cantaloupes, black strap molasses, beef, and tur- 001~5085/94/$3.00
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 549

(range, 4-14 mEq/day), and average urinary K+ output Effect of K+ intake on fecal K+ excretion. Be-
was 80.8 mEq/day (range, 66- 102 mEq/day). From these tween 1946 and 1954, Dempsey et al. measured fecal K+
results, we may conclude that under conditions of a nor- excretion in 3 1 patients with nongastrointestinal diseases
mal dietary K+ intake, about 90% of dietary Kf is ab- on a metabolic ward.” K+ intake was varied between 39
sorbed by normal subjects and that the major route of and 195 mEq/day, and fecal collections were started after
excretion of absorbed K+ is through the kidneys. It needs the subjects received a constant diet for 3-5 days. The
to be emphasized that such intake/output calculations values reported represented an average of two or more 6-
(90% of dietary Kf is absorbed) apply to net intestinal day fecal collections. These investigators interpreted their
absorption (net gain to the body) rather than to the data to show no change in fecal K+ output in response to
amount of K+ actually absorbed by the intestine. Because dietary K+ variation. However, when we reanalyzed their
K+ is present in salivary, gastric, biliary, and pancreatic data, we discovered a slight but statistically significant
secretions, actual K+ absorption is higher than intake/ direct relationship (Y = 0.44; P < 0.002) between dietary
output calculations might suggest. Two experiments de- K+ intake and fecal K+ output. The regression line indi-
signed for other purposes showed quantitatively similar cates that on average, fecal K+ increased 5 mEq/day for
results,9~‘” but these studies had relatively short balance each 50 mEq/day increase in intake.
periods and involved only one and three subjects, respec- The fecal response to low dietary K+ intake was stud-
tively. Other studies are difficult to use because the infor- ied by Squires and Huth.‘> They fed four normal volun-
mation is shown in complicated balance diagrams rather teers a diet containing < 1 mEq/day of K+. In 3 of the
than in tables.“,‘2 4 subjects, the average fecal K+ excretion at the end of
The influence of sex on net absorption of K+ has appar- the balance period was 3.6 mEq/day. We excluded one of
ently not been assessed in metabolic balance ward studies. their subjects from this analysis because he had diarrhea.
However, Holbrook et al. studied 12 men and 16 women These results indicate that fecal K+ excretion in abso-
during a l-week balance period at home.5 The average lute terms (mEq/day) changes relatively slightly as di-
K+ intake (2 SEM) was 74 + 2.6 and 54 & 2.6 mEq/ etary K + intake is varied over a wide range. However,
day for men and women, respectively. The average fecal if one were to express fecal K+ excretion as a percent of
Kf output was 12.0 + 0.5 and 8.5 + 0.5 mEq/day, intake, excretion would decrease as intake is increased
respectively. Thus, the men ingested somewhat more K+ above normal and would increase dramatically as dietary
in their diets and excreted somewhat more Kf in their Kf intake decreases to very low levels When evaluating
stools. The fractional absorption of K+ averaged 84% in fecal K+ excretion in disease states, it is important to
both men and women. carefully note the units of expression of fecal K+.
Effect of low K+ diet on urinary Kf excre- Summary of balance studies in normal sub
tion. Blahd and Bassett fed a diet containing 14 mEq/ jects. Fecal Kt averages about 10 mEq/day when nor-
day of K+ to a normal subject for 55 days.” At the end mal people ingest a diet containing 92.5 mEq of K+.
of this period, urine K+ had decreased from a control When dietary K+ intake is increased, fecal Kf increases
value of about 90 to about 15 mEq/day. In three normal only slightly, indicating that absorption increases almost
volunteers, Johnson et al. restricted dietary Kf to 9 mEq/ in direct proportion to increasing intake. It is therefore
day.‘j At the end of 10 days, the urinary K+ output was not surprising that in people whose renal Kt excretion
reduced from a control value of 81 to 16.7 mEq/day. is impaired, K+ toxicity can result from abnormally high
Lowe gave an electrolyte-free diet to six patients with Kf intake. When dietary K+ intake is severely restricted,
duodenal ulcer and measured urine Kf output daily for fecal K+ decreases to about 3.5 mEq/day, which presum-
14 days.14 Urinary K+ decreased to <lO mEq/day by ably represents obligatory fecal K’ excretion from intes-
day 4 and remained < 10 mEq/day for the duration of tinal secretions. Under normal conditions, urinary K+
the study. Squires and Huth measured daily urinary K+ excretion is equal to the amount of dietary Kt that is
output when normal subjects ingested specified levels of absorbed. When dietary Kt is essentially zero, obligatory
a low intake diet for 6-21 days.15 Urinary K+ excretion renal K+ losses amount to 5-10 mEq/day. By contrast,
decreased progressively with time, and our plot of their when dietary Na+ is restricted to near zero, the kidney
data (maximal urinary K+ conservation vs. dietary K+ can elaborate a urine that is virtually free of Na+.’
intake) indicates that when dietary K+ intake is zero,
obligatory renal Kf loss averages 6.3 mEq/day. Cumulative K+ Losses and Hypokalemia
During Dietary K’ Depletion
Several processes can impair the ability of the kidney to
conserve Kf; these include bicarbonaturia, water diuresis, When dietary K’ intake is restricted to near zero,
and natriuresis. 16 K+ is lost from the body because of continued Kt excre-
550 AGARWAL ET AL. GASTROENTEROLOGY Vol. 107, No. 2

ward. 8-10~15,20,21Fecal Kf excretion ranged from 3.7 to

24.8 mEq/day (mean, 10.1; SEM, 1.7; SD, 5.8). If the
highest observed value of 24.8 is considered an outlier,
the range of fecal K+ excretion in the other 11 normal
people is 3.7-14.0 mEq/day (mean, 8.8; SEM, 1.1; SD,
3.7). The cause of this rather wide (4-6-fold) variation
is not known. Because fecal weight and percent water
and solid content were not provided in these reports, it
is impossible to know if fecal Kf excretion in normal
people is correlated with these variables; it is also not
possible to know if the variation was because of differ-
ences in dietary fiber intake. It is interesting to note, for
purposes of comparison, that fecal weight is also highly
Duration of K depletion (days)
0 variable in normal people (from 31 to 195 g/day, a 6.3-
0 2 4 6 6 10 12 14 16
fold variation), presumably because of differences in fiber
Duration of K depletion (days)
intake22 or intestinal transit time.
Figure 1. Cumulative negative K+ balance induced by a zero K’ diet.15 Using the mean + 2 SD as an estimate of the upper
The zero K’ diet was prepared by treating a milk-based diet with a
limit of normality and excluding the possible outlier, a
K+ exchange resin and fed to four normal volunteers. Each symbol
represents one volunteer. The dietary Na+ content was variable. Data fecal K+ output of >16.2 mEq/day is abnormal. If the
shown represent the combined urinary and fecal K+ losses. The inset outlier is not excluded, the upper limit of normal is 2 1.7
shows the decrease in serum K+ in each subject.
mEq/day. These values can be used to assess whether or
not fecal K’ excretion is elevated in an individual pa-
tient. With such a wide range of normal, caution will
tion in stool and urine. In Figure 1, we have plotted be needed in interpreting differences in average results
cumulative K+ losses under these conditions for the four between small groups of normal people and small groups
normal subjects studied by Squires and Huth.i> K+ losses of patients with a disease process. Caution is also appro-
were greater at the onset of Kf restriction than afterward. priate when fecal K+ excretion is expressed as a fraction
By day 10, cumulative losses amounted to 175-220 of dietary K+ intake as previously explained.
mEq; in one subject, K+ loss was 300 mEq after 20 days
Fecal K+ Concentration in Normal Stool
of severe dietary Kf restriction. Although K+ losses of
Water
these magnitudes amount to only 5 % - 10% of total body
exchangeable K+, serum K+ concentrations decreased by The average fecal weight in normal people is 125
an average of 20% (as shown in the insert to Figure 1). g/day; because 75% of fecal weight in normal subjects
This suggests that extracellular K+ was depleted to a consists of water, normal subjects on average excrete
greater extent than intracellular K+. Therefore, besides about 95 g of fecal water per day.22 Because average fecal
Kf losses in stool and urine, the distribution of Kf K+ excretion is about 10 mEq/day, the K+ concentration
within and outside the cells is an important determinant in fecal water would be 105 mEq/L if all fecal K+ were
of serum K+. Factors that shift K+ into cells and thus in solution. The measured K+ concentration in fluid
favor the development of hypokalemia include insulin, obtained from normal stools by ultracentrifugation is
catecholamines, metabolic alkalosis, and possibly aldoste- 83 5 24 mEq/L, and the average concentration of Kf
rone. Factors that shift K+ out of cells into the extracellu- in stool water by in vivo dialysis is 95 + 36 mEq/L,23
lar fluid and would thus oppose the development of hypo- suggesting that the vast majority of fecal K+ in normal
kalemia include hypertonicity, exercise, infusion of stools is in fact in solution.
mineral acids such as sulfuric and hydrochloric acids, and
Intestinal Absorption and Secretion
intoxication with cardiac glycosides or succinylcho-
line.“.” Net Absorption of Dietary K’ by the Small
Intestine
Upper Limits of Normal for Fecal K’
Several groups have measured Kt output in ileos-
Excretion
tomy fluid. In three such studies in subjects who had
We were able to find reports of 12 normal people negligible amounts of ileum resected and were ingesting
who ingested a “normal diet” and had fecal Kf excretion a “normal” diet, Kf output ranged from an average of 3.6
measured for at least 5 days on a metabolic balance to 5.5 mEq/day.24-26 Unfortunately, the dietary intake of
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 551

K+ was not measured in these subjects, so it is not possi- Net K’ Absorption and Secretion of K’ by
ble to determine the net amount of Ke absorbed by the the Colon
small bowel. If we assume, for the sake of speculation, The colonic contribution to net gastrointestinal
that the dietary intake in these subjects was 70 mEq/ absorption of dietary K+ can be estimated in two ways.
day, then net small bowel absorption was about 65 mEq/ First, ileostomy data indicate that about 5 mEq/day of
day (93% of intake). As noted previously, actual absorp- K+ is unabsorbed in the small bowel, and this would
tion is higher than the balance calculations suggest. be delivered to the cecum if a colectomy had not been
Other investigators have attempted to quantitate the performed.24-26 Because K+ output in the stools of nor-
amount of unabsorbed Kf in the small bowel of normal mal people averages about 9 mEq/day, this would suggest
people by the slow marker perfusion method.*’ Subjects that the normal colon secretes about 4 mEq/day of K’.
are intubated with a double lumen tube; a solution con- Second, in the slow marker perfusion studies of Phillips
taining a nonabsorbable marker is slowly and constantly and Giller, terminal ileal K+ was 9.3 mEq/day and fecal
infused into the distal ileum via the proximal opening K+ excretion was 4.7 mEq/day.2” This study suggests
of the tube, and terminal ileal contents are aspirated via that the colon absorbed 4.6 mEq of K+ per day. It should
the distal opening of the tube. From the concentration be noted that the fecal weight and fecal K’ excretion in
of the nonabsorbable marker in aspirated terminal ileal these subjects was only about one half of the average
fluid, the volume of terminal ileal fluid can be calculated. normal value.
This volume multiplied by the concentration of an elec- Although the ileostomy and slow marker perfusion
trolyte in the aspirated fluid is equal to the amount of studies do not agree on whether the colon normally ab-
unabsorbed electrolyte reaching the terminal ileum and sorbs or secretes K+, both methods show that the contri-
is assumed to be equal to the amount of electrolyte not bution of the colon to K+ balance is relatively small; it
absorbed in the small intestine. The significance of possi- either absorbs or secretes about 4 mEq/day.
ble artifacts of such methodology has been debated,28 but
most investigators believe the method is valid. Phillips
Physiological Studies on K’ Transport In
Vivo
and Giller used this method to measure small bowel
balance of fluid and electrolytes in normal subjects. Postprandial K’ concentration profile. The con-
When dietary Kt intake was 70 mEq/day, terminal ileal centration of Kf has been measured at multiple sites in
Kf was 9.3 mEq/day, indicating a net absorption by the the small intestine after ingestion of a steak and water
small bowel of 60.7 mEq of K+ per day or about 85% mea13’ Polyethylene glycol (PEG) was included in the
of the dietary Kf intake.2’ This result is therefore in water part of the meal as a nonabsorbable volume marker.
general agreement with calculations in patients who have PEG concentration increased 1 O-fold as the meal traveled
had colectomy and ileostomy. distally through the small intestine because of water ab-
Some studies have also been conducted in ileostomy sorption from the meal. Even as water was being avidly
patients who had 30-120 cm of their ileum resected absorbed, the concentration of K+ decreased from about
(normal small bowel length is 350 cm); K+ output aver- 20 mEq/L in fluid aspirated from the duodenum to about
aged 12.7 mEq/day, more than double that in ileostomy 7 mEq/L in fluid aspirated from the mid-small bowel.
subjects who had negligible ileal resection.24 This sug- This means that the duodenum and jejunum absorbed
gests that the lower small intestine contributes to absorp- K+ even more rapidly than water.
tion of dietary K+. However, studies in patients with K+ transport during intestinal perfusion. Intesti-
more extensive resections (short-bowel syndrome)30 sug- nal transport in vivo can be studied by intubation of
gest that the proximal small bowel is the dominant site segments of the intestine with a multilumen tube. Test
of dietary Kt absorption. These studies have shown that solutions of known composition containing PEG as a
only 50 cm of remaining jejunum is required for net nonabsorbable volume marker are infttsed continuously
gastrointestinal absorption of dietary K+. By contrast, at through a proximal opening of the tube and collected at
least 100 cm of remaining jejunum is required for net distal sampling sites after traversing a defined length of
gastrointestinal absorption of dietary Naf. This may be intestine; water and solute movement .within an intesti-
because of a steep lumen to serum concentration gradient nal segment can be calculated using nonabsorbable
in the case of K+ but not Naf. Although the normal marker equations.i2 Potential difference (PD) between
proximal jejunum may not absorb Kf as avidly as the subcutaneous tissue and luminal fluid can be measured
“adapted” jejunum in patients with short-bowel syn- and is assumed to be the same as transrnucosal potential.
drome, these results emphasize the large capacity of duo- The average PD in the jejunum is -1 f 1 mV (lumen
denal and jejunal mucosa to absorb dietary K+. negative), in the ileum is -8 t 1 mV, in the proximal
552 AGARWAL ET AL. GASTROENTEROLOGY Vol. 107, No. 2

intestine but via an unknown route in the colon, where

the paracellular pathway is relatively tight.34

F Regardless
absorptive
of the mechanism
capacity of the intestine
of K+ absorption,
for K+ is relatively
the

E large. For example, when ileal absorption is plotted as a

H function of luminal concentration, the regression line for
g K + 36 is much steeper than that for calcium and ap-
Y
5 proaches that for fructose, whose absorption is carrier-
z
mediated.43
Rectosigmoid K+ transport by the dialysis bag
-1.0 I 1 I I 1 I I
0 5 10 15 20 25 30 technique. In this technique, a small Visking dialysis
Mean lumlnal K concentration (mEq/L) bag containing a test solution is introduced into the
rectum or rectosigmoid after a saline enema. *O,*’A thin
Figure 2. Regression lines for K’ transport in various regions of the
human intestine under experimental steady-state perfusion. Data on layer of endogenous fluid is assumed to surround and
K+ transport in the small intestine represent 3O-cm segments of jeju- bathe the bag. The dialysis membrane is highly perme-
num or ileum36; in the colon, the transport rates are for the entire
able to monovalent electrolytes, and the concentration of
organ. ” Data on colon K+ transport were reported as microequiva-
lents per minute but have been mathematically converted to milliequi- ions in the intermediate fluid layer rapidly equilibrates
valents per hour. +, net absorption; -, net secretion. with that inside the bag. Once this has occurred, the
concentration of electrolytes in the bag is assumed to be
the same as in the fluid surrounding the bag. PD can be
colon is - 12 2 2 mV, and in the distal colon is -3 1 + measured simultaneously by a calomel electrode through
3 mV.33 These different PD values are because of different a cannula within the dialysis bag. The method is sensitive
ion transport mechanisms and permeability characteris- because small volumes of the test solution can be held
tics in the different areas of the intestine. When cation at the rectosigmoid site for long periods. However, if
permeability is measured by lithium or 42K absorption, the dialysis bag restricts the movement of solutes, it can
the order of permeability is found to be jejunum > introduce errors in the estimation of equilibrium state
ileum > colon3* In the human small intestine, the cation across the mucosa. Presumably because of technical diffi-
permeability sequence is PK > PNa > PLi.34 culties, this method has not been applied in the proximal
Regression lines for net Kt transport as a function of colon.
luminal K+ concentration are shown in Figure 2.35,36 In Using this technique, Kf movement was zero when
all areas of the intestine, the rate of Kf absorption or luminal K+ concentration was about 45 mEq/L; K+ se-
secretion is highly dependent on luminal Kf concentra- cretion occurred when the luminal K+ concentration was
tion. The regression line crosses zero at a luminal concen- <45 mEq/L, and K+ absorption occurred when luminal
tration of 3.0 mEq/L in the jejunum, 4.8 mEq/L in the K+ concentration exceeded 45 mEq/L. The observed PD
ileum, and 9.5 mEq/L in the colon. In the small intestine, was about -37 mV. By the Nernst equation for passive
the available evidence suggests that Kf transport is pre- ion movement, the predicted equilibrium concentration
dominantly passive in response to electrochemical gradi- was only 17 mEq/L. Because the observed concentration
ents and solvent drag. In fact, K+ equilibrates so rapidly was more than twofold higher than the predicted concen-
across the small bowel mucosa that Kt concentration in tration, these results cannot be explained by passive diffu-
fluid aspirated from the end of a test segment accurately sion. The investigators discussed three possible explana-
predicts PD by the Nernst equation.37 Similarly, when tions for this higher than expected K+ secretion rate,
the entire colon is perfused in vivo, there is no evidence including mucus secretion, cell desquamation, and active
for active Kf transport. For example, the geometric mean K+ secretion by the epithelial cells of the rectosigmoid
of the proximal and distal colon PD is 21.1 mV33*38-41; mucosa. There was no evidence of excessive mucus secre-
when this value is used to predict the Nernst equilibrium tion when K+ secretion rates were high, and it seemed
K’ concentration of colonic fluid, the result is 10.1 mEq/ unlikely that desquamation was an adequate explanation.
L, which is close to observed values obtained by Devroede Therefore, active K+ secretion seemed most likely.*’
and Phillips35 and by Billich and Levitan. Although Further studies with the dialysis technique*’ showed
these results do not exclude a component of active K’ that there was a tendency for K+ secretion rate to decrease
transport by the colon, they suggest that the dominant as the luminal Naf concentration was reduced, although
force is passive diffusion. Presumably, passive diffusion this difference was not statistically significant. K+ secre-
is via the leaky tight junction pathway in the small tion rate was markedly enhanced when Naf was replaced
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 553

by rubidium, ammonium, or lithium. It is interesting tion. The contraction of volume within the colon causes
that the rectosigmoid mucosa absorbed lithium more the K+ concentration in luminal fluid to increase. Second,
rapidly than it absorbed Na+,*’ whereas with the perfu- active K+ secretion in the rectosigmoid could further
sion method, the entire colon absorbs Naf avidly but increase the Kf concentration in fecal fluid, assuming
does not absorb lithium to a measurable extent3*; the that such secretion is not dependent on sodium-rich lu-
explanation for this apparent discrepancy is not clear. minal fluid.
Present evidence in humans therefore supports active However, there remains a discrepancy because the K’
K+ transport in vivo only in the rectosigmoid. Presum- concentration in normal stool water of 83-95 mEq/L is
ably, the surface area of actively secreting mucosa and the twofold higher than the concentration of K+ in fluid
rate of active secretion are so small that active secretion of held until equilibration in the rectosigmoid by dialysis
Kf is not detected during perfusion of the entire colon. bags. Although the explanation for this discrepancy is
Although the dialysis bag studies indicate that the not clear, the following is suggested: (1) Obligation of
rectosigmoid mucosa is capable of active K+ secretion, K+ by anions in colonic contents; the poorly absorbed
these studies have not shown that the rectosigmoid ac- anions could originate from the diet per se or from bacte-
tively secretes K+ under normal physiological conditions. rial metabolism of carbohydrates that escape absorption
Such secretion might be dependent on exposure of the in the small bowel. (2) A component of colonic contents
rectal mucosa to a sodium-rich electrolyte solution as that is not usually included in experimental test solutions
would be present in people with diarrhea or ureterosig- might stimulate active K+ secretion; one such possibility
moid anastomosis but might not be present during expo- is NH4 .*‘I
sure to normal fecal material or when the rectum is
empty. Except for mucus, the rectal mucosa is not known K+ Transport In Vitro
to secrete a fluid that can be aspirated by suction on a
We were unable to find in vitro studies of Kt
tube as occurs in the stomach.
transport in the human small intestine, but two such
Bidirectional K’ fluxes. Using isotopic K+, bidi-
experiments have been conducted using the left side of
rectional Kf fluxes have been measured in the ileum and
44.45 the normal human colon.46,47 Both showed net K+ secre-
sigmoid colon of anesthetized human subjects in vivo.
tion under short-circuit conditions, which implies active
The results in the ileum were highly variable and only
K’ secretion. When Na+ was removed from the bath,
three subjects were studied, so no definite conclusion can
K+ secretion was eliminated, predominantly as a result
be reached. In the sigmoid colon of six subjects exposed
of a decrease in serosa-to-mucosa flux; this suggests Na+l
to a physiological test solution, K+ was secreted at a rate
Kf exchange.*’ We found no in vitro Ussing chamber
of 5 1 FEq. 10 min-’ . 100 cmp2; the mucosal/serosal flux
rate was 30 and the serosal/mucosal flux rate was 81 studies of the proximal human colon.

PEq. 10 min-’ . 100 cmb2. Assuming that the mucosal/ Wills et al., using current fluctuation analysis,48 noted
serosal flux is totally passive, the data suggest that the no increase in transmucosal resistance of the distal human
sigmoid is rather permeable to Kf, more so than would colon when Na+ and Cl- in a mucosal bathing solution
have been anticipated by the rate of lithium absorption were replaced with K+ and gluconate. The apical and
during perfusion of the entire colon.34 Whether this pas- basolateral PD measured by microelectrodes also did not
sive flux occurs via a transcellular or paracellular route change. If the apical membrane of the human distal colon
is unknown. Because the colon paracellular route is be- was only conductive to Na+ and Cl-, then the removal
lieved to be relatively tight and anion-selective, these of these ions from the bathing solution would have in-
results may argue for a transcellular route for passive K+ creased the transmucosal resistance. Thus, the investiga-
flux. tors reasoned that K+ channels must exist in the apical
Mechanisms for high K+ concentration in normal membrane. However, there was no direct measure of K’
stool water. As previously noted, normal stool water fluxes, and studies were not performed in the presence
contains 83-95 mEq/L of K+ depending on the method of K+ channel blockers. Sandle and M&lone found that
of analysis. Two known physiological factors can be in- amiloride (1 0m4 mol/L) increased the membrane resis-
voked to partly explain this dramatic concentration gra- tance ratio (apical/basolateral membrane resistance) in the
dient between plasma and the lumen of the distal colon. distal human colonic mucosa by 130%.49 They reasoned
First, the colon absorbs about 90% of the water delivered that the increase was lower than expected if amiloride-
to it from the ileum but only a relatively small fraction sensitive Na’ channels were the main ifonic conductance
of K’. Kt absorption in the colon is retarded by electrical at the apical membrane. Therefore, they suggested the
gradients generated by active electrogenic Na+ absorp- existence of Kf channels. However, tetraethylammonium
554 AGARWAL ET AL.
and barium chloride, which block K+ channels, did not
alter the electrical properties of the membrane.
These in vitro studies indicate active K+ secretion in
the distal human colon but give no insight into the
quantitative physiological importance of active Kf secre-
tion in relation to the quantity of Kf absorbed or secreted
by passive mechanisms. Because active Kf secretion can-
not be detected when the entire colon is perfused in vivo,
it seems likely that the magnitude of active K+ secretion
by the normal colon is quite small in relation to the
magnitude of passive K+ movement in response to elec-
trochemical gradients. However, the presence of some
active K+ secretion as shown by in vitro studies suggests
the possibility of increased active K+ secretion in disease
states that might be quantitatively significant.
The sparcity of in vitro studies in the human intestine
prompted us to review in vitro experiments in the animal
intestine. Experiments in the neonatal porcine jejunum”
suggest both active K+ absorption and active Kf secre-
tion; these presumably nearly cancel each other out in
the normal intestine. The active processes were shown
in the presence of various inhibitors; e.g., the active ab-
sorptive process was unmasked by ouabain. Although the
investigators found evidence that a major component of
K+ movement is across the paracellular pathway, they
concluded that an imbalance between active K+ secretion
and impaired active K+ absorption might be responsible
for excess fecal K+ losses in rotavirus enteritis in piglets.
In vitro studies on K+ transport in the colon have
been reported from several laboratories. For example, the
entire rabbit colon actively secretes Kf, although the
mechanisms between the proximal and distal colon dif-
fers51 In the rat, the proximal colon actively secretes K+
by an electrogenic mechanism whereas the distal colon
actively absorbs K+ by an electroneutral mechanism.52
The interspecies variation in the direction and mecha-
nisms of active K+ transport indicates that results from
experimental animals cannot be extrapolated directly to
humans. However, the fact that in vitro colonic K+ trans-
port in several animal species is heterogeneous with sig-
nificant segmental differences suggests that such segmen-
tal differences may also exist in humans.
Hormone and Drug Effects
Mineralocorticoids
In normal subjects by balance technique. Rel-
man and Schwartz studied three normal subjects on a
low, medium, and high Na+ diet while they consumed
normal amounts of dietary K+ (61-72 mEq/day).’ In
the control period (4-5 days), the stool K+ was 3.7, 6.9,
and 5.2 mEq/day, respectively. DOCA (desoxycorticoste-
rone) was administered for 7 - 11 days in a dosage of 10
GASTROENTEROLOGY Vol. 107, No. 2
mg twice a day intramuscularly. The fecal K+ output
increased slightly to 4.5, 8.2, and 7.5 mEq/day, respec-
tively. The Naf content of the stool decreased, especially
in the subjects ingesting a medium and high Naf diet.
Huth et al. studied the effect of DOCA on fecal K+
output in four metabolic balance studies in three normal
subjects.s3 All subjects received a high Naf diet. The
subjects were depleted of Kf by ingesting a diet con-
taining < 1 mEq/day of K+, and DOCA was then admin-
istered intramuscularly in a dosage of 20 mg/day for 5-
6 days. The fecal Kf output increased from 6.1, 19.0,
9.2, and 5.5 mEq/day in the four subjects to 6.9, 24.0,
9.5, and 6.4 mEq/day, respectively. If we average the K+
excretion from both reports, we obtain a baseline fecal K+
output of 7.9 + 5.2 mEq/day that increased to 9.6 ? 6.5
mEq/day after administration of pharmacological doses
of DOCA (P < 0.05).
August et al. measured the effect of daily injections
of 6 mg aldosterone in one normal subject who was
eating a diet containing 75 mEq Na+ and 84 mEq K+.21
Fecal collection periods were 7 days in the control period
and 22 days in the aldosterone period. Fecal K+ excretion
increased from 3.7 in the control period to 12.4 mEq/
day under the influence of aldosterone. Fecal Naf excre-
tion was 0.2 and 0.4 mEq/day in the two periods, respec-
tively.
Thus, high doses of mineralocorticoids increase fecal
K+ excretion in normal subjects. The magnitude of the
response in different people varies from 0.3 to 8.7 mEq/
day.
In a patient with primary aldosteronism. In one
of the first reports of primary aldosteronism caused by
adrenal adenoma, Mader and Iseri studied a patient whose
dietary sodium intake was 60-80 mEq/day and K+ in-
take was about 150 mEq/day plus K+ supplements as
needed for hypokalemia.54 During a l-month period, av-
erage fecal Kf output was 16.3 mEq/day, which is higher
than in most normal subjects. The patient was not re-
studied after removal of the adenoma.
In subjects with ileostomy. These studies, sum-
marized in Table 1, are limited in value because dietary
intake of Na+, Kf, and other components was not mea-
sured.55-5s In some instances, results were expressed only
as a ratio of Na+ and Kf concentrations in ileostomy
fluid “; in some studies, the number of subjects was
sma11.57 Therefore, it is not surprising that the results
are sometimes contradictory. However, taken as a group,
these experiments suggest that mineralocorticoids may
reduce the amount of Na+ and water and increase the
amount of K+ excreted in ileostomy effluent.
Assuming that aldosterone increases K+ excretion in
ileostomy fluid, the site of this small intestinal effect is
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 555

Table 1. Effect of Mineralocorticoids on K+ Transport in lleostomized Patients

No. of
Reference Mineralocorticoid Dose and duration subjects Results Comments

55 9&udrohydrocortisone 2 mg orally on the evening 20 Decrease in Na’/K’ Cannot determine whether

before the last 3 from 20 to 13.9 the change in ratio was
ileostomy collections because of increased K’
excretion or decreased
Na+ excretion
56 9a-fludrohydrocortisone l-2 mg orally 8 No consistent effect on K+ concentration was
Na+, K+, or water increased in 3 of 6
output subjects receiving 2 mg
Scr-fludrohydrocortisone;
K’ output was also
increased in two subjects
57 Daldosterone 2 mg intravenously for 3 4 Decrease in ileostomy The differences were not
days output from 914 to statistically significant,
815 g/day and an perhaps because of the
increase in K+ output small number of patients
from 8.6 to 10.4 who were studied
mWday
58 Mineralocorticoid antagonist 1 There was an increase
(spironolactone) in ileostomy output
from 1040 to 1217
g/day and a
decrease in K’
output from 31 to 19
mWday

unknown. Jejunal perfusion studies indicate that hyperal- corticoids decrease Naf absorption and increase K+ secre-
dosteronism has no effect on Na+ and Kf absorption59360; tion.
this suggests that any effect of aldosterone on the small Only one group of investigators has examined the ef-
bowel of subjects with ileostomy may be mediated in fect of mineralocorticoids in the rectosigmoid. Using the
the ileum rather than the jejunum. We did not find dialysis bag technique, they found increased Naf absorp-
experiments that evaluated the effect of aldosterone on tion and increased K+ secretion. The K+ secretion paral-
PD across the small bowel mucosa. leled the PD between the mucosa and subcutaneous tis-
In children with ileoanal anastomosis. Schwarz sue. 65 In a separate report not summarized in Table 2,
et al. studied three children with colectomy and ileoanal Edmonds and Godfrey66 administered one or two doses
pull-through (surgery performed for total colonic Hirsch- of aldosterone (500 pg intravenously) and found a pro-
sprung’s disease).” Fecal output was measured when the gressive increase in the electronegative potential that par-
patients were on a normal salt intake and when dietary alleled the decrease in urine Na+/K+ ratio.
salt intake was severely restricted for 5 days. During salt Time course. After intravenous administration of
restriction, average serum aldosterone levels increased aldosterone, rectosigmoid PD increased by 4 hours,
from a control value of 166 to 501 ng/dL, fecal K+ peaked at 6 hours, and returned to normal at 18 hours.‘”
output increased from 8.9 to 12.6 mEq/day, fecal sodium In two patients with colonic interposition for resected
output decreased from 62 to 54 mEq/day, and the weight esophageal cancer, Shields et al. noted stimulation of K+
of fecal discharge decreased from 466 to 406 g/day. This secretion within 30-90 minutes after a 250..pg intrave-
study, like those in subjects with ileostomy, supports the nous bolus of aldosterone followed by an infusion of I
notion that aldosterone increases the K+ output from the l.Lg/min.“3 These results suggest that aldosterone acts
small bowel. within a few hours and that its effect ends within 24
In the normal colon and rectosigmoid by experi- hours of administration of pharmacological doses.
mental methods. As summarized in Table 2, studies on Levitan studied five normal subjects after administra-
the effect of mineralocorticoids on the colon have yielded tion of 9a-fluorohydrocortisone and noted stimulation
different patterns of response.62-6s Some colon perfusion of water and salt absorption 24 hours later. 62 This is a
experiments have shown that mineralocorticoids increase longer duration of action than Edmonds and Godfrey
Na+ absorption but have no effect on the rate of Kf noted with aldosterone. How quickly 9-a-tluorohydro-
secretion, whereas others have suggested that mineralo- cortisone or other synthetic mineralocorticoids act on the
556 AGARWAL ET AL. GASTROENTEROLOGY Vol. 107, No. 2

Table 2. Different Patterns of Mineralocorticoid Effect on Colorectal Absorption and Secretion of Kt

Intestinal No. of
segment studies Methods and magnitude of effect

Pattern A: increased Na+ absorption

and no effect on K+
Levitar? Colon 5 Colon perfusion in normal subjects with and without 9a-
fluorohydrocortisone; effect on K+ negligible (secretion of
1.4 mEq/h with and without) and Na+ absorption
increased by 15 mEq/h
Pattern B: decreased Na+
absorption and increased K’
secretion
Shields et aLe3 Transverse colon 2 Colon perfusion before and after intravenous administration
of aldosterone; Na+ absorption decreased by 2.5
mEq. h-l.30 cm-l and K+ secretion increased 1.4
mEq h-l. 30 cm-l
Shields et al.64 Colon 1 Colon perfusion before and after removal of adrenal
adenoma; K+ secretion decreased by 6.4 mEq/h and
Na+ absorption increased by 14.1 mEq/h after removal
of the adenoma to correct hyperaldosteronism
Pattern C: increased Na+ absorption
and increased K+ secretion
Jenkins et al.65 Rectum 2 Rectal dialysis in children with secondary
hyperaldosteronism (congenital chloridorrhea) compared
with normal children; children with chloridorrhea had
higher Na+ absorption by 157 nmol.min-1.cm-2, higher
K+ secretion by 45.5 nmol.minl~cm-*, and higher PD
by 54 mV
Jenkins et al.65 Rectum 3 Rectal dialysis in children with adrenal insufficiency before
and after mineralocorticoid replacement; Na+ absorption
increased by 87 nmol~min-i~cm-2, K+ secretion
increased by 25 nmol~min-1~cm-2, and PD increased
from 19 to 43 mV
Jenkins et aLe5 Rectum 2 Rectal dialysis in children with receptor defect for
aldosterone compared with normal children; children with
the defect had a lower Naf absorption by 97
nmol~min-1~cm-2, lower K+ secretion by 31.5
nmol.min-1.cm-2, and lower PD by 31 mV

human colon is not known. Although these steroids act
on the same mineralocorticoid receptor, their pharmaco-
kinetics may influence the time course of action.
Summary of effects of mineralocorticoids.
preceding studies are not always consistent but in general
suggest that pharmacological doses of mineralocorticoid
or states of hyperaldosteronism increase the amount of
Kf delivered by the small bowel to the colon (i.e., they
reduce small bowel absorption of K+) and stimulate K+
secretion by the colon and rectum. The magnitude of
the increased fecal K+ excretion in normal intact people
varies between 0.3 and 8.7 mEq/day. The mechanism by
which aldosterone causes excess fecal K+ excretion is
uncertain. In the colon and rectum, increased K+ secre-
tion in response to aldosterone is associated with an in-
crease in lumen-negative PD, so some or all of the en-
hanced K+ secretion may be mediated passively in
response to this electrical gradient. The mechanism by
which aldosterone enhances PD probably involves stimu-
lation of Na+/K+ adenosine triphosphatase. We found
no evidence that aldosterone stimulates active K+ secre-
tion or Kf channels, but by the same token, there is no
The evidence against such possibilities.
Glucocorticoids
The effect of glucocorticoids on fecal Kf excretion
was studied by Danowski et a1.67 Varying doses of corti-
sone (50- 1000 mg/day) or adrenocorticotropin ( 10 - 100
mg/day) were administered for 3-5 days to hospitalized
patients with nongastrointestinal diseases. The dietary
intake of Kf was not explicitly stated. In the control
period (47 collection periods), K+ output was 8.1 ? 5.3
mEq/day. After cortisone and adrenocorticotropin, the
K+ outputs were 10.7 ? 7 and 8.7 + 5.7 mEq/day,
respectively. The data are difficult to interpret because
of the varying doses and duration of cortisone or adreno-
corticotropin administered. However, the results appear
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 557

to exclude any marked effect of glucocorticoids on fecal from 25 to 40 g/day and found that average fecal Kt
K+ output, output in seven patients increased from a control of 11
Crake et al. studied the effect of intrajejunal (100 mg/ to 41 mEq/day. There was no significant change in stool
L) cortisol in normal subjects using a double-lumen, balloon weight.75 Evans et al. administered an Na+ resin in a
occlusion intestinal perfusion technique.@ Intraluminal cor- dose of 15 g every 6-8 hours by mouth together with
tisol increased glucose, sodium, Kf , and water absorption. 30 g as an enema to five patients with acute renal fail-
Whether K+ absorption was increased secondary to solvent ure .76 The therapy lasted 3-5 days. We excluded one
drag or because of a primary effect on K+ transport is patient from the analysis who died 18 hours after admin-
unclear. Intravenous cortisol had no effect.@ istration of the resin. The resin was recovered in the
Sandle et al. studied the effects of a single intravenous feces by washing with distilled water. The resin was
lOO-mg dose of cortisol in 17 normal subjects using subsequently weighed, and electrolytes bound to it were
in vivo rectal dialysis.‘” Five hours after glucocorticoid measured after elution with 2N hydrochloric acid. Al-
administration, the PD increased from -37 to -54 mV, though the theoretical cation-binding capacity of the
sodium absorption increased from 3.1 to 5.4 resin was 3.4 mEq/g, the in vivo K+ binding ranged
l,trnol. cm-* . h-l, and K+ secretion increased from 2 to from 0.5 to 1.2 mEq/g of resin. The results were similar
3.2 j.tmol.cm-2 . h-‘. All changes were statistically sig- to that of another study” in which the in vivo Kf bind-
nificant. Similar results were found with methylpredniso- ing was 1.3 mEq/g. In one patient who died, resin was
lone. Thus, systemic glucocorticoids appear to mediate recovered from various parts of the intestine. The mea-
rectal K+ secretion when the rectal mucosa is exposed sured Kf binding (mEq/g) increased progressively from
to a sodium-rich electrolyte solution. Studies examining 0.17 in the stomach to 0.41 in the jejunum and 0.57
the effect of cortisol on the whole colon under perfusion in the descending colon, suggesting that K+ binding
conditions were not found. increases along the length of the gut.
In a patient with hyperkalemia, Elkinton et al. admin-
Amiloride istered an enema of 10% carboxylic ammonium exchange
Schiller et al. noted stimulation of colonic K+ resin in water in a dose of 250 mL twice a day (50 g
secretion from 0.4 to 0.7 mmol/h when perfusing the resin per day).‘* Fecal Na+ and K+ output increased from
entire colon with lo-* mol/L (0.1 mmol/L) amiloride 1 mEq/day each to 8 and 29 mEq/day, respectively; the
solution.39 This was despite a decrease in PD from -46 increment in fecal Kf corresponds to 0.56 mEq/g resin.
to -30 mV in the distal colon (but no change in PD in In one normal subject, Evans et al. administered an en-
the proximal colon). Amiloride reduced Naf absorption ema of 30 g of Na+ resin.‘” The K+ binding (based
rate from 20 to 15 mEq/h. The mechanism of increased on analysis of sequential bowel movements) increased
colonic Kf secretion with amiloride is not apparent. San- progressively with time: 0.11 at 3 hours, 0.33 at 9 hours,
dle et al.” studied the effect of amiloride (1 mmol/L) and 0.39 mEq/g at 18 hours. In contrast., oral resin bound
using the dialysis bag technique. There was no effect on 0.5- 1.2 mEq Kf/g resin, suggesting that resin enemas
rectal K+ secretion rate, even though sodium absorption are less effective than resin by mouth.
rate and PD were significantly reduced. Because enemas presumably get exposed only to the
colon and because only about 4-9 mEq of K’ enters the
Cation Exchange Resins colon per day, one might think that maximal K+ binding
by enema would be limited to 4-9 mEq/day. The fact
Cation exchange resins are cross-linked polymers
that enemas can bind up to 28 mEq/day is therefore
with acid and basic structural units. In vitro, resins have
somewhat surprising. Perhaps enemas remove K+ from
a higher affinity for divalent than monovalent cations. the fluid bathing the colonic mucosa and thereby stimu-
Before ingestion by mouth or as an enema, resins have late higher K+ secretion than normal because of higher
been exposed to a cation, usually Hf or Na+, that binds electrochemical gradients between plasma and colonic
to all cation binding sites. Because the resin binds about luminal fluid.
3.5 mEq cation per gram of resin and because the dose The clinical effectiveness of resin therapy per se for
of resin averages 30 g and may be administered several hyperkalemia is uncertain because multiple modalities
times a day, resin therapy entails ingestion of a substan- are usually used at the same time. It is not certain
tial load of H+ or Na+. In the small bowel and colon, whether or not resin plus sorbitol is more efficacious than
the resin exchanges part of its Na+ or H+ for K+, and sorbitol alone.” Rectal administration of resin together
fecal K+ excretion is thereby enhanced.71-74 with sorbitol has been associated with colonic necrosis
In a metabolic balance study, Greenman et al. admin- and perforation,80,81 possibly because af the hypertonic
istered an acid exchange resin orally in a dose ranging nature of the sorbitol.ai
558 AGARWAL ET AL. GASTROENTEROLOGY Vol. 107, No. 2

Table 3. Potassium Balance in a Patient With Chronic Diarrhea

K+ intake Fractional Balance

Balance (mEc/ Stool K’ output Net absorption absorptiona Urine K’ output (mEo/ Serum K’ level
period day) (mEo/day) (mEo/day) (%I (m&/day) day) (mEo/L)

3 145 57 88 61 82 +6 -
4 145 59 86 59 87 -1 3.3
5 60 50 10 17 35 -25 2.3
6 141 29 112 79 68 +44 3.5
7 141 51 90 64 80 +10 -

NOTE. Data from Harrison et aI.”

‘Fractional absorption is defined as net absorption divided by dietary intake multiplied by 100.

Diarrhea higher than urine K+ excretion in normal subjects who

Metabolic Balance
We were able to find only one case report in which
a patient with long-term diarrhea was studied by the
metabolic balance technique.82 In January 1942,
year-old woman with secretory diarrhea and malabsorp-
tion syndrome caused by lymphosarcoma of the small
intestine was studied during 16 consecutive metabolic
balance periods, each 4-6 days, with stool collection
periods separated by carmine red. As shown in Table 3,
during balance periods 3 and 4, her dietary K+ intake
was 145 mEq/day, fecal Kf excretion averaged 58 mEq/
day, average fractional K+ absorption (defined as net ab-
sorption divided by dietary intake multiplied by 100)
was 6O%, and she was in near perfect K+ balance. The
high K+ intake during these periods was because of a
high protein diet. During balance period 5, the dietary
protein intake was reduced to 75 g/day and dietary K+
intake therefore decreased to 60 mEq/day. During this
period of normal K+ intake, fecal Kf excretion remained
abnormally high at 50 mEq/day so that she absorbed
only 10 mEq/day of K+; her urine Kf excretion decreased
only modestly and she was in negative Kf balance, which
was associated with severe hypokalemia. During periods
6 and 7, her K+ intake was increased, she went into
positive Kf balance, and the serum Kf level returned to
normal.
Further insight is derived by considering the fractional
absorption of the extra K + in the diet because intake
was increased from a normal level of 60 to 141 mEq/day
(compare balance periods 5 and 7). On a 60 mEq/day
diet, stool Kf was 50 mEq/day and fractional absorption
was 17%. When dietary K+ was increased by 81 mEq/
day (to 141 mEq/day; period 7), stool K+ was only 1
mEq/day higher than when K+ intake was 60 mEq/day.
Thus, the extra K+ intake of 81 mEq/day was absorbed
almost completely (99%).
During the development of hypokalemia in period 5,
urinary K+ excretion was 35 mEq/day, which is threefold
are subjected to severe dietary K+ restriction. The reason
her kidneys failed to conserve K+ to a greater extent is
not clear. Intrinsic renal disease cannot be excluded; be-
cause sodium balance data were not presented, the vol-
a 44- ume and aldosterone status of the patient are unclear.
Some possible reasons for failure of renal KC conservation
in patients with diarrhea are discussed later.
This unique and careful case study shows the interplay
of diet, fecal K+ excretion, and urine K+ excretion as
determinants of K+ balance during long-term diarrhea.
The patient’s fecal Kf losses were high and apparently
fixed at about 50 mEq/day. When diet K+ was normal
at 60 mEq/day, she absorbed only a small amount of K+
and her kidneys did not conserve K+ well enough to
prevent negative K+ balance. Negative K+ balance was
prevented when her dietary K+ intake was high because
there was a net intestinal absorption of 99% of the extra
K+ taken in her diet.
K+ Deficits in Diarrhea
Using the isotopic dilution method, Blainey et
al. measured total exchangeable K+ in 12 patients with
steatorrhea, many of whom had diarrhea andlor bulky
stools.83 For comparison, they studied 24 control subjects
who did not have diarrhea. The patients weighed an
average of 20% less than the controls, presumably be-
cause of malnutrition secondary to malabsorption and/or
decreased food intake. Exchangeable K+ averaged 40%
less in the steatorrhea and diarrhea group than in the
controls, which is a statistically significant difference.
The investigators point out that some of the reduced
exchangeable Kf may have been because of loss of lean
body mass. To the extent that the weight loss reflected
a loss of body muscle, exchangeable K+ would decrease
correspondingly. On the other hand, loss of weight be-
cause of a loss of fat would not be associated with reduced
exchangeable K+. Because it was not known to what
extent weight loss in these patients was caused by loss
of muscle vs. fat, it was not possible from these single
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 559

measurements to know whether the markedly reduced Table 4. Fecal K+ Excretion in Experimental Diarrhea in

exchangeable Kf was caused by loss of lean body mass, Normal Volunteers

negative K+ b a 1ante caused by excessive fecal K+, or a Stool K+

combination of these two processes. Experimental weight concentration K’ output
agent n (g/day) (mFq/L) (mEq/24 hours)
To further evaluate this question, Blainey et al. admin-
istered KC1 by mouth to four of the patients for 6-10 PEG 3 589 15 9
Phenolphthalein 6 567 42 24
weeks and then repeated the measurement of exchange-
Sodium sulfate 3 686 36 22
able K+. Before KC1 therapy, the average exchangeable Sorbitol and
K+ was 1494 mEq; this value increased to 2510 mEq lactulose 6 633 33 21

after KC1 treatment. There was no change in body weight NOTE. Data from Hammer et al.84
during the KC1 treatment period and therefore presum- n represents the number of subjects. Each subject had 4day consecu-
ably no change in lean body mass. The serum Kf in tive stool collections; the first day specimen was discarded.

one of these four patients was 1.8 mEq/L before KC1

treatment; serum values were not provided for the other
patients. Blainey et al. concluded that the marked in- water from the intestine and probably represents the
crease in exchangeable K+ associated with oral KC1 ther- purest form of osmotic diarrhea. Even when PEG caused
apy in the absence of an increase in body weight indicated fecal water losses as high as 1.5 L/day, average fecal K’
that the markedly reduced exchangeable Kf before KC1 losses did not exceed 13 mEq/day (normal average is 9-
treatment was not merely the result of a loss of muscle 10 mEq/day). This shows that diarrhea does not cause a
mass but was also caused by primary K+ depletion. marked fecal K+ wastage by virtue of a washout effect;
It thus appears that exchangeable Kf can be reduced the normal human intestine continues to absorb the vast
for two reasons in patients with diarrhea. First, if malnu- majority of dietary K + intake even when moderately
trition is present, this will lead to negative nitrogen and severe diarrhea is present.
Kt balance commensurate with the loss of muscle mass. Table 4 shows fecal K+ excretion in experimental diar-
The exchangeable K’ deficit would be intracellular, and rhea caused by various agents.a4 In each experiment, the
the serum Kf concentration would presumably remain average fecal weights were around 600 g/day, so the
within normal limits. Second, when net intestinal K+ severity of diarrhea was comparable. Fecal K+ output
absorption is reduced enough to lead to negative K+ was 2-3-fold higher when diarrhea was induced by in-
balance caused by high fecal K+ losses and/or low K+ gestion of sodium sulfate or poorly absorbed sugars than
diet, exchangeable K+ will decrease. Assuming that ni- in diarrhea induced by PEG. This is most likely because
trogen balance remained normal, there would be no de- poorly absorbed sulfate or organic anions derived from
crease in lean body mass. This mechanism of low ex- bacterial metabolism of unabsorbed sugars obligate the
changeable K+ would reduce both the intracellular and retention of K+ within the bowel lumen. Diarrhea in-
extracellular K+ pools, so the patient might become hy- duced by phenolphthalein also causes more fecal Kf ex-
pokalemic. Obviously, the two mechanisms might coex- cretion than diarrhea caused by PEG. Phenolphthalein is
ist in the same patient. It is theoretically possible that the believed to cause diarrhea by inhibition of active sodium
loss of lean body mass might mitigate the development of chloride absorption and stimulation of active chloride
hypokalemia in a patient with excessive fecal Kf losses secretionR5; increased fecal K+ secretion might therefore
if K+ released from muscle breakdown was retained in result from obligation of K+ by unabsorbed or secreted
the extracellular fluid rather than excreted in the urine. chloride or by electrical gradients generated by active
chloride secretion. If phenolphthalein increases 5’-cyclic
Determinants of Fecal K+ Excretion in adenosine monophosphate, the latter might promote ac-
Diarrhea tive K+ secretions’; however, the available evidence does
Fecal electrolyte output has been studied in nor- not suggest that mucosal 5’-cyclic adenosine monophos-
mal subjects in whom diarrhea was induced experimen- phate increases after phenolphthalein.s”~x7
tally with specific agents whose mechanism of action is We previously concluded that pharmacological doses
reasonably well established.84 Because water and electro- of mineralocorticoid or states of hyperaldosteronism in-
lytes were provided to compensate for fecal losses, plasma creased fecal K+ excretion in otherwise normal people
aldosterone level was presumably not elevated in subjects by 0.3-8.7 mEq/day. Unfortunately, only a few studies
undergoing these experiments. One such agent is PEG, have been performed to evaluate whether or not patients
which is osmotically active, nonabsorbable, and un- with diarrhea have secondary hyperaldosteronism and, if
charged; it induces diarrhea by inhibiting absorption of so, to what extent it increases fecal Kf excretion. Three
560 AGARWAL ET AL.
studies have shown that urinary or plasma aldosterone
levels are elevated in infants or children with diar-
rhea, 61S88,89especially when such children are salt-re-
stricted.” In eight adult patients with short-bowel syn-
drome, serum aldosterone levels averaged 48 ng/dL with
values in control subjects ranging between 3 and 22 ngl
dL.90 The degree to which plasma and urinary aldosterone
levels were increased in these patients with diarrhea are
comparable with the increases found in primary hyperal-
dosteronism and secondary hyperaldosteronemic states
such as cirrhosis with ascites and congestive heart failure.
Although we found no measurement of aldosterone in
patients with cholera, it seems likely that patients with
such severe diarrhea would have hyperaldosteronism sec-
ondary to volume contraction. Guerrant et al. adminis-
tered spironolactone (100 mg orally) to 15 patients with
cholera who were partially volume-repleted.” During the
control period, mean fecal Na+ excretion (normalized to
a 24-hour period even though study periods were 8 hours)
was 526 mEq/day and Kf output was 136 mEq/day.
After spironolactone, fecal Na+ excretion increased by
74 mEq/day and fecal K+ excretion decreased by 7 1 mEq/
day; stool volume was unchanged at about 4.8 L/day.
Assuming that the effect of spironolactone was solely
caused by inhibition of the effect of aldosterone, these
studies suggest that aldosterone promotes intestinal Naf
conservation and intestinal K+ wastage in cholera. The
amount of Na+ conservation (74 mEq/day) was almost
exactly the same as the amount of Kf wastage (71 mEq/
day); the mechanism underlying such an apparent Naf/
K+ exchange is not known.
The Guerrant et al. study therefore suggests that in
cholera, hyperaldosteronism causes a reduction in fecal
Na+ and a comparable increase in fecal K+. The magni-
tude of this effect was large (7 l-74 mEq/day), approxi-
mately equal to the amount of K+ ingested in a normal
diet. Because the patients had 4.8 L/day of stool, the
results suggest that for every liter of stool in cholera,
hyperaldosteronism increases fecal Kf and decreases fecal
Na+ by about 15 mEq. Although we find no reason to
question the accuracy of these findings, the study has
certain limitations, including the fact that serum aldoste-
rone levels were not measured and there was no control
group of patients who did not receive spironolactone.
Furthermore, it is hard to understand why aldosterone
would have such a dramatic effect in cholera but such a
minimal effect on ileostomy K+ output and colonic K+
secretion during colonic perfusion in normal subjects
(Tables 1 and 2).
Table 5 summarizes our conclusions concerning the
mechanisms of increased fecal K+ excretion in patients
with diarrhea. Presumably, variation in one or more of
GASTROENTEROLOGY Vol. 107, No. 2
Table 5. Mechanisms of Increased Fecal K+ Excretion in
Diarrhea
Major effects
K+ obligation by poorly absorbed anion ingested by mouth (e.g.,
sulfate, phosphate)
K+ obligation by organic anions derived from bacterial
metabolism of unabsorbed carbohydrates
K+ obligation by unabsorbed or actively secreted chloride
Increased K+ secretion caused by secondary hyperaldosteronism
Minor Effect
Washout secondary to increased fecal water output
Some possible mechanisms that have apparently not been
investigated in humans
Malabsorption of K+ caused by small bowel disease
Obligation of K+ by unabsorbed fatty acids in patients with
steatorrhea
Ingestion of K+ salts administered to prevent K+ depletion
Increased active K+ secretion or decreased active K+ absorption
Increased passive K+ secretion in response to abnormally high
electrical gradients or change in intestinal permeability
Induction of Kt channels by polypeptides or toxins
these mechanisms is responsible for the wide range of
fecal K+ concentrations in patients with diarrhea, even
when patients with the same disease and similar stool
volumes are considered.
Speculation on Renal Kf Wasting in
Diarrhea Caused by Secondary
Hyperaldosteronism
Assuming that a patient was volume-depleted be-
cause of NaCl losses in stool, the serum level of aldoste-
rone would increase. However, aldosterone promotes re-
nal K+ excretion only if Naf delivery to the distal
nephron is high. Because NaCl depletion is the factor
that initiates the increase in aldosterone levels in a patient
with diarrhea, such patients would not be expected to
have high NaCl delivery to the distal nephron. Also, if
a patient ingests enough NaCl to cause delivery of NaCl
to the distal nephron, the secondary aldosteronism should
abate. Therefore, on theoretical grounds, it could be ar-
gued that secondary hyperaldosteronism caused by diar-
rhea is probably not a contributor to the development
of renal K+ wastage in people with diarrhea. However,
secondary hyperaldosteronism caused by diarrhea could
cause renal K+ wastage if mechanisms were at play that
caused Na+ delivery to the distal nephron in spite of
volume depletion. Alkalosis, excess water intake with
water diuresis, and intrinsic renal disease are three such
possibilities. Also, short-term loads of NaCl, either via
diet or intravenous infusion, might permit transient renal
Kf wastage because the signals and transport processes
that regulate the aldosterone effect do not down-regulate
instantaneously.
Unfortunately, the renal excretion of K+ has not been
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 561

measured often enough in patients with diarrhea to allow of these patients turned out to have malignant endocrine
a critical evaluation of these speculations. The only rele- tumors, and they were excluded from further analysis.
vant report we discovered is that by Guerrant et al. in In the remaining 311 patients, many different diagnoses
patients with cholera who were studied after partial vol- were ultimately established, including microscopic and
ume repletion.” These workers found that spironolactone collagenous colitis, inflammatory bowel disease, celiac
caused urinary K+ excretion to decrease from a control sprue, diabetic neuropathy, bacterial overgrowth syn-
of 44 to 30 mEq/day (Na+ in urine increased from 76 drome, surreptitious laxative abuse, pancreatic insuffi-
to 135 mEq/day). Thus, under these specific conditions, ciency, bile acid malabsorption, carbohydrate malabsorp-
secondary hyperaldosteronism caused by diarrhea appears tion, and irritable bowel syndrome. As shown in Table
to have resulted in renal K+ wastage. 6, in spite of moderately severe diarrhea (average stool
wt, 707 g/day), only 10% of the patients had a serum
Frequency of Hypokalemia
K’ < 3.5 and only 3.2% had a serum K+ 5 3.0. These
In the short-term and severe diarrhea of Asiatic frequencies were altered only slightly by the exclusion
cholera, 6% of patients are hypokalemic on admission to or inclusion of patients who were taking diuretics or Kf
the hospital and 24% are hypokalemic 24 hours later.“’ supplements or had previous gastrointestinal surgery.
From a review of case reports, the frequency of hypoka-
Fecal K+ Losses in Different Diarrhea1
lemia in several of the chronic diarrhea1 syndromes associ-
Diseases
ated with neuroendocrine tumors has also been estimated
by other investigators. Hypokalemia, defined as serum As previously noted, the concentration of K+ in
K+ < 3.5 mEq/L, occurs in 83% of patients with the normal stool water averages 83-95 mEq/L depending
vipoma syndrome, 2 1% of patients with malignant carci- on the method of study. When diarrhea develops, the
noid syndrome, and 10% of patients with medullary fecal K+ concentration decreases; in patients with volu-
carcinoma of the thyroid.“’ We found no previous tabula- minous diarrhea, such as may be found in severe cholera,
tion of the frequency of hypokalemia in patients with the Kf concentration in fecal fluid is only modestly
diarrhea caused by villous adenoma of the rectum. In our higher than in plasma. Several examples of fecal K’ con-
review of 21 reports on this disorder,“*-“* we found 27 centration in diarrhea are provided in Table 4. Because
cases; 78% had a serum K+ < 3.5, and 63% had a serum fecal K+ concentration varies with stool volume, a com-
K+ I 3.0. parison of fecal K+ losses in different diarrhea1 diseases
We were not able to find information in the literature must somehow be related to stool volume. To see if any
on the frequency of hypokalemia in patients with chronic particular disease state was associated with a low or high
diarrhea caused by nonmalignant diseases. Therefore, we fecal K+ excretion, we plotted fecal K’ concentration
analyzed the 314 patients with chronic diarrhea who and fecal K+ output in individual patients with cholera”’
were referred to us between July I985 and September as a function of fecal volume; these results in cholera
1992 either because the diagnosis was difficult to estab- were used as a reference standard against which other
lish or because the symptoms were incapacitating. Three diseases could be compared. In plots that will not be

Table 6. Stool Weight, Fecal K+, and Serum K+ Levels in Patients With Nonendocrine Causes of Chronic Diarrhea

Average Percent with Percent with

Total no. Stool K’ serum K’ serum K’ serum K+
of Stool weight output level level < 3.5 level 5 3.0
patients &/day) (m&/day) (mEq/L) mWL mWL

All patients 311 707 2 48 28.5 t 1.2 4.10 2 0.3 10.0 3.2
Patients taking diuretics
excluded 283 714 ? 52 28.1 -c 1.3 4.12 -c 0.03 9.2 2.8
Patients taking K+ supplements
excluded 285 685 t 51 27.2 2 1.2 4.11 -+ 0.03 a.4 3.2
Patients taking K’ supplements
or diuretics excluded 267 697 2 54 27.1 ? 1.3 4.12 2 0.03 8.6 3.0
Patients with no past
gastrointestinal surgery 186 589 2 44 28.9 + 1.5 4.11 -+ 0.04 8.6 4.3
Patients taking no K+
supplements or diuretics and
with no past gastrointestinal
surgery 154 542 2 48 26.6 t 1.6 4.13 2 0.04 7.8 4.5
562 AGARWAL ET AL. GASTROENTEROLOGY Vol. 107, No. 2

reproduced, we found that fecal Kf outputs in ulcerative

colitis,115X116microscopic colitis,“’
and secretory diarrhea
caused by laxative abuse118 were similar to that in pa-
tients with cholera of equal stool volume. In 3 of 5
patients with villous adenoma of the rectum with diar- .
rhea 94-98 fecal K+ output was somewhat lower than in .
-
patients with cholera. Perhaps this is because the diarrhea
fluid originates at a low level in the colon, thereby .
Y
allowing less opportunity for passive K+ secretion. Only
in patients with islet cell tumor and diarrhea (vipoma
syndrome)118-126 r=-0.263
was K+ output usually higher than in p < o.oaN
l!...,...,...,...,...,...,..,, .
patients with equally severe cholera. The explanation for 0 20 40 60 80 loo 120 140
the increased K+ output in vipoma syndrome is not Fecel K excretion (mEq/day)

known, although it is interesting to note that vasoactive

Figure 3. Correlation of fecal K+ excretion and serum K’ concentra-
intestinal polypeptide directly stimulates aldosterone se- tion in patients with nonendocrine causes of chronic diarrhea. See
cretion’*‘; the high K+ output in vipoma syndrome text for a description of this patient group.
might also be caused by vasoactive intestinal polypeptide
stimulation of active K+ secretion, although we know of
no direct evidence to support this speculation. losses. This must mean that in many patients with long-
term diarrhea, the dietary intake of K+, the distribution
of K+ between cells and extracellular fluid, and/or the
Correlation of Serum Kf Concentration urinary excretion of K+ play a major role in the develop-
and Fecal K+ Excretion ment of hypokalemia. Of course, this does not deny the
As pointed out previously and in Figure 1, when dominant role that fecal K+ losses can play when such
people ingest a diet that is severely deficient in K+, losses are extraordinarily high. For example, patients
hypokalemia develops after a loss of only 5% - 10% of with chronic diarrhea caused by vipoma have very large
total body exchangeable K+ (about 175 -300 mEq). fecal K+ outputs averaging 179 mEq/day in 12 reported
Therefore, it seems reasonable to assume that K+ losses patients,118-126 and 83% of patients with vipoma are
of 175-300 mEq in patients with diarrhea would also hypokalemic on admission to the hospital.93
lead to a strong predisposition to hypokalemia. A nega- Hypokalemia associated with villous adenoma of the
tive K+ balance in diarrhea is primarily caused by exces- rectum deserves special comment. We were able to find
sive K+ losses in stool and secondarily influenced by the five case reports 94-98 in which both serum Kf concentra-
amount of Kf in the diet and the degree of renal K+ tions and fecal K+ excretion were measured. The average
conservation; whether or not hypokalemia actually devel- serum Kf level was 2.7 mEq/L, and the average fecal
ops also depends on the distribution of K+ between intra- Kf output was 55 mEq/day. By comparison, in our pa-
cellular and extracellular fluid compartments. Unfortu- tients with long-term diarrhea (Figure 3), we had 13
nately, with the rare exception described previously, patients with fecal K+ outputs between 50 and 60 mEq/
dietary K+ intake and urine Kf excretion have not been day in whom the average serum K+ level was 4 mEq/L;
accurately measured in patients with chronic diarrhea. none of them had a serum K+ concentration < 3.0 mEq/
Nevertheless, it might be possible to determine the L. Therefore, it seems likely that factors other than fecal
role of increased fecal K+ excretion in the development K+ excretion play major roles in the development of
of hypokalemia by correlating fecal K+ excretion and hypokalemia in patients with rectal villous adenoma. In
serum Kf concentration. We have done this in Figure reading the case reports, it seems clear that these patients
3 for our 3 11 patients with chronic diarrhea; the data were quite ill, often with hypotension caused by volume
show a highly significant statistical correlation between depletion. We suspect their dietary K+ intakes were ex-
fecal K+ excretion and serum K+ concentration. There- tremely low and serum aldosterone levels were very high.
fore, as expected, the amount of Kf lost in stool is one
factor that influences the development of hypokalemia.
Summary of Factors That Promote the
However, there is a great deal of scatter around the re-
Development of Hypokalemia in People
With Diarrhea
gression line; some patients are hypokalemic even though
their fecal K+ output is only slightiy above normal, and If renal K+ conservation were normal (< 10 mEq/
others are normokalemic in spite of very large fecal K+ day excreted in urine as discussed previously) and dietary
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 563

Table 7. Speculation on Factors That May Promote the per se; metabolic disturbances caused by coexisting renal
Development of Hypokalemia in People With disease will not be considered.
Diarrhea

1. High fecal K+ output as seen mainly in secretory diarrhea and

Ureterosigmoid Anastomosis
augmented by secondary hyperaldosteronism
When urine is diverted into the sigmoid, patients
2. Low dietary K’ intake
3. Failure of kidneys to conserve K+ normally (~10 mEq/day) often develop metabolic acidosis and hyperchloremia,
A. Secondary hyperaldosteronism combined with a factor that which can be explained by rectosigmoid absorption of
causes Na’ delivery to the distal tubules. The secondary
NHd+ and absorption of urine Cl- in exchange for se-
hyperaldosteronism is caused by volume contraction due to
high fecal Na+ and water losses. The factors that cause Na+
creted HC03-.‘“’ Bacteria can convert urine urea to
delivery to the distal tubule (in spite of volume contraction) NH,, the absorption of which can lead to encephalopathy
include short-term oral or intravenous salt loads (not enough if the patient has coexisting liver disease.
to replete volume status and thereby reverse
Because urine contains about 90% of K+ ingested in
hyperaldosteronism), metabolic alkalosis, or the excretion of
other poorly absorbed anions such as ketoanions and D the diet and because urine K+ concentration is usually
Lactate much higher than serum K+ concentration, it might be
B. Polydipsia,” resulting in water diuresis, which increases
logical to assume that the rectosigmoid would absorb
urinary K+ excretion
C. Magnesium depletion129.130 urine K+, the patient would not be able to excrete a
4. Shift of K’ from ECF to ICF dietary K+ load, and the patient would therefore become
A. B2 agonists (e.g., epinephrine) released in response to hyperkalemic. However, on the contrary, these patients
volume contraction
B. Metabolic alkalosis
tend to develop hypokalemia’32S133 and total body K+
C. ? aldosterone depletion.13* Therefore, these patients must have either
a reduced Kf intake or excessive Kf losses because of
“Severe polydipsia and polyuria may occur in patients with chronic
diarrhea.12’ Polydipsia apparently does not contribute to the diarrhea the ureter-sigmoid anastomosis. Because reduced food
but by increasing urinary flow rate may contribute to urinary K+ losses. intake has been noted in only a few case reports,135,136 it
seems necessary to conclude that the anastomosis some-
how enhances external K+ losses above what K+ losses
K+ were normal at about 75 mEq/day, fecal K+ excretion would have been if the ureter drained externally without
would have to exceed 65 mEq/day before a patient would contact with the rectosigmoid mucosa.
be in negative K+ balance. However, many patients with The only experiments that shed direct light on the
hypokalemia caused by diarrhea have fecal K+ excre- mechanism of external K+ losses in this condition were
tion < 65 mEq/day as shown in Table 3 and Figure 3. conducted by Annis and Alexander in 1952.‘“’ They
Therefore, it seems highly likely that reduced K+ intake, studied two patients with an intact gemtourinary system
failure of normal renal conservation, or shifts of K+ from but who had a colostomy such that the sigmoid colon
ECF to ICF must play a role in the development of and rectum were isolated between a proximal stoma and
hypokalemia in people with diarrhea. the anus. Because the fecal stream was diverted from
In Table 7, we have listed the factors that promote the rectosigmoid, the bacterial flora in the segment is
the development of hypokalemia in people with diarrhea uncertain. Histologically, the mucosa was normal. The
and speculated on some of the pathophysiological factors experiment entailed instillation of the patients’ urine into
that might lead to failure of renal conservation and shifts the rectosigmoid for a 3-hour period, after which the
of K+ out of the ECF. If our speculations are accurate, contents were voluntarily voided via the anal canal. Five
high fecal sodium losses with volume contraction, poly- experiments were conducted in the two subjects. Some,
dipsia,“’ magnesium depletion,‘29,‘30 and acute NaCl but not all, urine samples were analyzed; average results
loads are factors that can contribute to the development of available data were as follows (in mEq/L unless other-
of hypokalemia. wise specified): Na+, 91; K+, 26; Cl-, 137; NH*+, 55;
and urea, 2050 mg%. Although osmolality was not mea-
Ureted-lntestinal Anastomosis sured, the electrolyte and urea content alone would ac-
The management of carcinoma of the bladder, count for an osmolality of approximately 684 mOsm/kg.
bladder exstrophy, neurogenic bladder, or urinary incon- The average volume of instilled urine was 160 mL,
tinence may require the insertion of the ureter into the and the volume recovered 3 hours later was 175 mL.
intestine. This may result in different metabolic compli- (Because a volume-recovery marker wa.s not used, it is
cations, depending on the intestinal site of ureteral inser- possible that some fluid was not recovered from the recto-
tion. Our discussion will be limited to metabolic compli- sigmoid). Thus, the sigmoid colon did not absorb urinary
cations caused by urinary diversion into the intestine water, perhaps because of its hypertonicity. In addition,
564 AGARWAL ET AL.
because urea is poorly absorbed by the colon,42 it could
prevent water absorption or induce water secretion os-
motically. The extent to which bacteria in this isolated
sigmoid would metabolize urea to NH, is uncertain.
In the fluid recovered from the rectosigmoid, the con-
centrations of Na’ and Cl- had decreased (in comparison
to their concentration in the instilled urine), but the
concentration of K+ had increased from 26 to 29 mEq/
L. The fact that the K+ concentration increased as volume
increased means that the sigmoid secreted K+ against a
rather steep concentration gradient. The total amount of
K+ instilled into the sigmoid as urine was 3.9 mEq, and
5.2 mEq was recovered in the voided specimen 3 hours
later (net K+ secretion, 1.3 mEq/3 hours). These results
suggest that rectosigmoid K+ secretion is one factor that
probably plays a role in the development of hypokalemia
in these patients. The mechanism of K+ secretion is
uncertain because PD was not measured.
As previously noted, dialysis bag studies have shown
that the rectum actively secretes K+ when NaCl and KC1
mixtures are instilled into the bag. Salas-Co11 et al. have
reported that NH4 + included in the dialysis bag causes
a marked increase in rectal K+ secretion rate. *’ Because
NH*+ and K+ appear to share a common transporter in
the rat ileum,‘38 it is theoretically possible that high
concentrations of urinary NH*+ in the rectosigmoid lu-
men might inhibit K+ absorption and thereby unmask
active K+ secretion into the lumen.
Ureteroileal Anastomosis
Although diversion of the ureter into a segment
of ileum as a conduit can result in hyperchloremic acido-
sis, this complication occurs much less commonly than
with ureterosigmoid ana.stomosis.139-149 Total body K+
and serum K+ levels are apparently not significantly al-
tered by this procedure. 134
Ureterojejunal Anastomosis
As in ureterosigmoid anastomosis, ureterojejunal
cutaneous anastomosis may be complicated by metabolic
acidosis; however, the metabolic acidosis is hypochlore-
mic instead of hyperchloremic, and patients tend to de-
velop hyponatremia (which is not seen in ureterosigmoid
anastomosis).lsO Also, these patients tend to develop hy-
perkalemia rather than hypokalemia,“’ presumably be-
cause the jejunum readily absorbs K+ when the luminal
concentration exceeds 5 mEq/L.
The etiology of hyponatremia and hypochloremia is
unknown, but one possibility can be suggested. If the
patient produces hypotonic urine in response to drinking
water, the jejunum would avidly absorb the water as the
GASTROENTEROLOGY Vol. 107, No. 2
urine traverses through it, thus preventing excretion of
the ingested water load. Hypochloremia without hypona-
tremia could occur because of jejunal absorption of un-
measured urinary anions such as phosphate.
Intestinal Adaptation in Chronic
Renal Failure
Metabolic Balance Studies
Under normal conditions, people absorb most of
the K+ they ingest in their diet and excrete an equal
amount in the urine. When severe renal failure super-
venes, renal K+ excretion should decrease; unless dietary
K+ were commensurately reduced, severe hyperkalemia
would be expected. Surprisingly, severe hyperkalemia of-
ten does not develop. In part, this is because surviving
nephrons develop an increased capacity to excrete Kf
into the urine. However, in 1965 and again in 1967,
Hayes et al. reported metabolic balance studies on pa-
tients with end-stage renal disease (many of whom were
being treated by hemodialysis) and found that fecal K+
excretion was abnormally high.‘s’V152 For example, in one
such patient ingesting 100 mEq/day of K+, fecal K+
excretion was 73 mEq/day. Several other patients ex-
creted more than 50 mEq/day in the stool, which is twice
as high as fecal K+ excretion in phenolphthalein-induced
diarrhea (Table 4), higher than K+ excretion after treat-
ment with cation exchange resin and higher than in the
vast majority of patients with chronic diarrhea (Figure 3).
From results obtained in patients with varying degrees of
renal failure, the investigators suggested that increased
fecal K+ begins to contribute to maintenance of K+ bal-
ance when the creatinine clearance decreases below 5 mL/
min; this is the same point at which residual nephrons
develop their maximal capacity to secrete K+ into the
urine. The fact that successful renal transplantation was
accompanied by a dramatic reduction in fecal K+ excre-
tion suggested that intestinal adaptation was somehow
related directly to the uremic process.
In regard to the mechanism by which fecal K+ excre-
tion was increased in their patients with severe renal
failure, Hayes et al. made several observations on intesti-
nal function. First, fecal Kt excretion decreased dramati-
cally when dietary K+ was restricted. This suggested to
the investigators that the primary mechanism for in-
creased fecal Kf excretion was decreased intestinal ab-
sorption rather than increased intestinal K+ secretion.
Second, dietary Na+ restriction or spironolactone had no
effect on fecal K+ output, thereby suggesting that this
effect was not mediated by aldosterone. Third, increased
stool K+ excretion was paralleled by increased stool Na+
excretion (as in diarrhea), which the investigators used
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 565

as additional evidence that hyperaldosteronism was not 46 t 9 mEq/day. In a third study,ls5 eight patients with
the mediator of the high fecal K+ excretion. severe chronic renal failure not requiring dialysis were
The fourth and most interesting observation was that examined. On a 41 .l mEq/day K+ diet, the fecal K+
patients with high fecal K+ excretion also had abnor- excretion was 11.8 mEq/day and urinary K+ excretion
mally high fecal weight, up to 500 g/day. In fact, there was 27.2 mEq/day. In none of these three reports were
was an excellent correlation between fecal weight and normal subjects studied as controls.
fecal K+ excretion, and the apparent fecal K+ concentra- Thus, in three studies other than that reported by
tion in stool averaged about 117 mEq/kg. In patients Hayes et al., average fecal K+ excretion rates in patients
whose stool weights were more than 300 g/day, fecal with uremia were 5.7, 14.4, and 11.8 mEq/day. Two of
water content was 83% (normal, 75%), indicating that these average results are somewhat higher than the aver-
most of the increase in fecal weight was caused by in- age result in normal subjects collected from the litera-
creased water rather than increased solids. Even though ture, and one average result is somewhat lower. These
stool weights were abnormally high and percent water three studies taken together suggest that fecal K+ excre-
content was elevated, the patients did not have increased tion may be slightly higher in patients with uremia than
stool frequency. Most had a single soft but formed stool in normal subjects. In none of these subsequent studies
every 1 or 2 days, and 6 of the 21 patients actually were data on fecal weight presented, and we were unable
complained of constipation. Fecal fat excretion was <3 to find other reports on fecal weight in patients with
g/day. No abnormalities in motility were detected by chronic renal failure, including a survey of reported studies
barium meal studies or carmine red transit time. performed to evaluate calcium balance in patients with
The close relationship between increased fecal water uremia. Apparently, it is the usual practice in metabolic
output and fecal Kf and Na+ excretion in the patients balance laboratories to homogenize stool in water before
reported by Hayes et al. raises the question of which was analysis, so the weight of feces per se is not determined.
the primary event. Because increased fecal water output Because of the sparcity of reported data that might be
does not wash out K+ in significant amounts, it seems able to confirm or refute the concept of intestinal adaptation
unlikely that a defect in intestinal water absorption could in severe renal failure, we asked Dr. Jacob Lemann at the
explain high fecal Kf excretion. Therefore, high fecal Medical College of Wisconsin to analyze the results of his
Kf excretion in these patients probably resulted from metabolic balance studies in patients with chronic renal dis-
Kf malabsorption or increased K+ secretion. Because Kf ease. His studies were performed for purposes of measuring
is mainly absorbed in the small bowel, K+ malabsorption calcium balance’5”,157; Kf balance was also measured but has
would probably reflect a change in small bowel function; not been reported. He and his colleagues studied eight pa-
increased K+ secretion would more likely originate in tients with severe chronic renal failure (not on dialysis) whose
the colon. An increase of 50 mEq K+ in fecal fluid, along average serum creatinine level was 8.0 mg/dL, average creati-
with a monovalent anion, would obligate a minimum of nine clearance was 12.5 mL/min, and average serum K+
300 mL of water to maintain isotonicity. This assumes concentration was 4.8 mEq/day. K+ intake (normal whole
that the fecal K+ is in solution and that there is no food) averaged 63.4 mEq/day, fecal K+ excretion averaged
increase in fecal Na+. Therefore, it is not surprising to 10.0 mEq/day, and urine K+ excretion averaged 49.9 mEq/
find increased fecal water output in patients who excrete day. Five normal subjects were studied contemporaneously.
50 mEq of K+ in their stool. Their average results were serum Kt concentration, 4.2 mEq/
Taken at face value, the data just reviewed provide L; dietary K+, 77.9 mEq/day; fecal K+, 7.4 mEq/day; and
strong evidence that severe chronic renal failure somehow urine K+, 63.9 r&q/day. Fecal weight was not recorded.
induces a marked increase in fecal K+ excretion and that Although it is not clear why average fecal K+ excretion was
this plays an important role in preventing hyperkalemia. lower in these normal subjects than the average result from
However, other reports have not confirmed the results of normal subjects reported in the literature, the data suggest
Hayes et al. In one study, which was not reported in that patients with uremia excrete slightly more (2.4 r&q/
detail, fecal K+ excretion averaged only 5.7 mEq/day in day) K+ in their feces than do normal subjects (Jacob Le-
eight patients with chronic renal failure.‘53 In a second mann, personal communication, Novem;ber 1993).
study designed to examine the effect of aldosterone on We conclude that patients with uremia probably have
K+ and water metabolism in chronic renal disease, nine higher fecal K+ excretion than normal. subjects as origi-
patients with varying degrees of renal failure were studied nally suggested by Hayes et al. However, the Hayes et
in a metabolic ward.15* When administered a diet con- al. proposal that the increase in fecal excretion is marked
taining an average of 63 mEq/day of Kf, fecal Kf excre- (up to 70 mEq/day) and contributes an important Kt
tion was 14.4 + 3.0 mEq/day and urinary excretion was excretory pathway in severe uremia has not been con-
566 AGARWAL ET AL. GASTROENTEROLOGY Vol. 107, No. 2

firmed by subsequent metabolic balance studies. One by studies of rectal K+ secretion using the dialysis bag
possible explanation for the discrepancy is that the pa- technique. Martin et al. found that K+ secretion in the
tients studied by Hayes et al. may have had more severe rectum was increased in patients with chronic renal insuf-
renal failure than the patients studied by other investiga- ficiency. 160 This was associated with an elevation of lu-
tors. Another possibility is a difference in some compo- men-negative PD. Na+ and water absorption were simi-
nent of the diet. Finally, it is possible that the patients lar to results in control subjects. Cl- absorption or
studied by Hayes et al. had K+ malabsorption caused by secretion rate was not reported. Mean plasma aldosterone
something other than or in addition to uremia. Unfortu- level was higher in the patients with renal insufficiency
nately, it is not possible to determine which, if any, of than in control subjects, but the difference was not statis-
these possible explanations is correct. tically significant. A possible mechanism for increased
rectal Kf secretion is the high transepithelial PD, but
Colonic K+ Secretion in Animals With it is difficult to understand why PD was elevated when
Renal Insufficiency sodium absorption was not increased. One possibility
The studies by Hayes et al. prompted experiments would be active Cl- secretion, but it would be hard to
in rats with renal insufficiency caused by 70% ablation explain why active Cl- secretion would elicit K+ secre-
of their renal mass.158 Colonic K+ secretion was studied tion but not reduce Na+ absorption. Sandle et al. found
during perfusion of a physiological electrolyte solution. twofold higher rates of rectal Kf secretion in eight pa-
The effect of previous exposure to varying dietary K+ tients with chronic renal failure than in 14 subjects with
intake was evaluated. When animals with renal insuffi- normal renal function.” Rectal Na+ absorption rate and
ciency had been previously fed 5 mEq . kg-‘. day-’ of PD were not elevated, so the high K+ secretion in their
Kf, their rate of colonic K+ secretion was similar to that patients did not fit the pattern of response induced by
in controls. However, when animals with renal insuffi- aldosterone (Table 2). Increased K+ secretion persisted
ciency had been fed 15 mEq *kg-‘. day-’ of K+, colonic in the presence of amiloride, which inhibited rectal Naf
K+ secretion tripled. This increased colonic K+ secretion absorption and reduced PD. Rectal K+ hypersecretion in
was associated with a marked increase in mucosal Na+/ their patients was not associated with abnormalities in
K+ adenosine triphosphatase concentration, an increase plasma aldosterone concentration, plasma or total body
in transepithelial PD, and increased colonic absorption content of K+, or acid-base disturbances. In a subsequent
rate of sodium and water. This pattern of response is report, 16’ Sandle et al. showed that high rectal K+ secre-
similar to the response to aldosterone. The increased co- tion also occurred in patients with renal failure on perito-
ionic K+ secretion was probably mediated at least in part neal dialysis and hemodialysis. They suggested that the
by the elevated PD. rate of rectal K+ hypersecretion depends on the amount
Although this study in rats has been interpreted as of K+ delivered to the mucosal sites of K+ transport,
supporting the notion of intestinal adaptation in renal which they postulate to vary with dietary Kf intake and
insufficiency, three qualitative differences should be plasma K+ concentration. It seems difficult to reconcile
noted. First, the dietary K+ intake needed to bring out this suggestion with the observation that total body K+
increased colonic K+ secretion in rats was quite large. and serum K+ concentration are not elevated.
A K+ intake of 15 mEq. kg-’ .day-* in 300-g rats is These studies have shown that rectal K+ secretion is
comparable with a K+ intake of 1050 mEq/day in a 70- increased in patients with chronic renal disease under
kg patient. Second, in patients with chronic renal disease, the experimental conditions associated with the dialysis
increased fecal Kf excretion was associated with de- bag technique. It is not known whether this is mediated
creased intestinal absorption of water (high fecal water by cation exchange or K+-anion secretion. The mecha-
output), whereas high colonic K+ secretion in rats was nism by which this hypersecretion is triggered has not
associated with elevated rates of water absorption. Third, been elucidated; the pattern of ion transport and electri-
in patients with chronic renal disease, Na+/K+ adenosine cal events seems inconsistent with a response to aldoste-
triphosphatase activity in rectal mucosa is norma1159; in rone, and plasma aldosterone concentrations are not ele-
rats with renal insufficiency and high K+ intake, Na+/ vated in most patients with uremia,” including those
Kf adenosine triphosphatase is high. on hemodialysis. 162 If the hypersecretion is triggered by
high mucosal site K+ content as suggested by Sandle et
Rectal K+ Secretion in Patients With al., it would seem to be a response to K+ overload rather
Chronic Renal Disease than a response unique to the uremic process. One other
The metabolic balance studies by Hayes et al. and possible trigger mechanism involves NHb+. In chronic
the studies in rats after renal ablation were followed renal failure, where blood urea concentration is very high,
August 1994 PATHOPHYSIOLOGY OF POTASSIUM TRANSPORT IN HUMANS 567

urea would presumably equilibrate across the permeable large loose stools if indeed this were part of a consistent
upper small intestine. When this urea-rich fluid is moved adaptation to renal failure.
into the colon, the urea would be metabolized to NH*+.
NH4+ might then block K+ absorption or stimulate K+ Summary
secretion.40 This mechanism of increased rectal K+ secre- When normal people ingest 90 mEq/day of K+
tion in uremia was suggested by one of the reviewers in their diet, they absorb about 90% of intake (81 mEq)
during the editorial process. and excrete an equivalent amount of K+ in the urine.
Although rectal Kf secretion by the dialysis bag tech- Normal fecal K+ excretion averages about 9 mEq/day.
nique appears to be increased in patients with chronic The vast majority of intestinal K+ absorption occurs in
renal disease, the clinical significance of this increase is the small intestine; the contribution of the normal colon
uncertain for three reasons. First, it is not known how to net Kf absorption and secretion is trivial. Kf is ab-
much mucosal surface area is involved in the hypersecre- sorbed or secreted mainly by passive mechanisms; the
tory state. The rate of rectal Kf hypersecretion in chronic rectum and perhaps the sigmoid colon have the capacity
renal failure amounts to about 1.5 pmol . h-’ . cm-*. If to actively secrete Kf, but the quantitative and physio-
this persisted indefinitely, the rate of hypersecretion logical significance of this active secretion is uncertain.
would be 36 pmol .day-’ . cm-*. Assuming that the hu- Hyperaldosteronism increases fecal K+ excretion by
man colon has a surface area of 1886 cm’ *’ and that about 3 mEq/day in people with otherwise normal intes-
the entire colon was hypersecreting at the same rate, tinal tracts. Cation exchange resin by mouth can increase
hypersecretion of Kf might increase fecal K+ excretion fecal K + excretion to 40 mEq/day. The absorptive mecha-
by 68 mEq/day. On the other hand, if only 100 cm* of nisms of K+ are not disturbed by diarrhea per se, but
rectum were hypersecreting, fecal Kf excretion might fecal K+ losses are increased in diarrhea1 diseases by unab-
be increased by only 3.6 mEq/day. A second question is sorbed anions (which obligate K+), by electrochemical
whether the rectum would actively secrete or hyperse- gradients secondary to active chloride secretion, and
Crete KC in the absence of rectal fluid that is rich in probably by secondary hyperaldosteronism. In diarrhea,
NaCI. Such fluid presumably is not present in the rectum total body Kf can be reduced by two mechanisms: loss
of patients with uremia. Third, rectal Kf hypersecretion of muscle mass because of malnutrition and reduced net
might diminish as the concentration of Kf in feces in- absorption of K+; only the latter causes hypokalemia.
creases. The dialysis bag studies have been conducted Balance studies in patients with diarrhea are exceedingly
with balloon K+ concentrations of lo-45 mEq/L, rare, but available data emphasize an important role for
whereas the K’ concentration in normal stool is 83-95 dietary Kf intake, renal K+ excretion, and fecal K+ losses
mEq/L. It is possible that such high fecal K+ concentra- in determining whether or not a patient develops hypo-
tions would mitigate the effect of a rectal K+ hypersecre- kalemia. The paradoxical negative Kt balance induced
tory process. by ureterosigmoid anastomosis is described. The concept
that fecal Kf excretion is markedly elevated in patients
Conclusions on Adaptation with uremia as an intestinal adaptation to prevent hyper-
kalemia is analyzed; we conclude that the data do not
In the final analysis, the clinical significance of convincingly show the existence of a major intestinal
intestinal adaptation in uremia can only be examined by adaptive response to chronic renal failure.
the metabolic balance method. Hayes et al. reported very
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Received July 6,1993. Accepted December 14,1993.
Address requests for reprints to: John S. Fordtran, M.D., Depart-
ment of Internal Medicine, Baylor University Medical Center, 3500
Gaston Avenue, Dallas, Texas 75246.
Supported by U.S. Public Health Service grant 5ROl-DK37172-05
from the National Institute of Diabetes and Digestive and Kidney
Diseases and by the Southwest Digestive Disease Foundation.
The authors thank Diana Santa Ana for her help in preparing the
manuscript and Jacob Lemann, Michael Emmett, Lawrence Schiller,
Kenneth Fine, Heimo Wenzl, and Judy Suneson for their helpful sug-
gestions.