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The consequences of potassium depletion
THE CONSEQUENCES
OF POTASSIUM
L. G. WELT, M.D., W. HOLLANDER, JR., M.D.* AND UT. B. BLYTHE, M.D.**
DEPLETION
From she Department
of Medicine,
tine, Universityof North Carolina (Received
for publication
School of Medi-
Dec. 16, 1959)
CHAPELHILL,N.C.
P
OTASSIURl is the major intracellular cation and, as such, must play a key role in the interrelationships between cell structure and function. It is, therefore, not surprising that a deficit of this mineral is accompanied by alterations in cellular activity and anatomic integrity. These disturbances occur in many organs and systems; the structural lesions may be described not only in conventional pathologic terms but in relation to alterations in molecular and ionic composition as well. The functional disturbances are many and vary from gross muscle paralysis to subtle changes in renal tubular activity. In fact, potassium depletion may be manifested by: impaired neuromuscular function that may vary from mild weakness to frank paralysis; alterations in gastric secretions, intestinal dilatation, and ileus; abnormalities of the myocardium with disturbed electrocardiographic patterns, conduction defects, and altered sensitivity to digitalis; abnormal functioning of the kidneys with impaired tubular secretion of para-aminohippurate (PAH), alterations in acidification, an inability to concentrate the urine appropriately, occasional depression in filtration rate, and a probably increased susceptibility to pyelonephritis; a disturbance in the regulation of the volume of the extracellular compartment which must, in part, be mediated via the kidneys; disturbances in acid-base equilibrium which can be related in part to certain features of renal dysfunction, but which may be due in greater measure to the consequences of the cell deficit of potassium and the transfer of hydrogen ions from the extracellular fluid to the cell; polydipsia which may be independent of the renal concentrating defect; disturbances in carbohydrate tolerance and other alterations in intermediary metabolism; changes in neuromuscular irritability which presumably reflect the consequences of disturbances in the usual relationships between calcium, pCOz, and pH; and no doubt many other functional derangements which are yet to be documented and understood. *Markle Scholar in Medical Science. **Fellow, Life Insurance Medical Research Fund. 213
214
WELT,
HOLLANDER,
AND
J. Chron. Dis. March, 1960
BLYTHE
P.4THOGENESIS
The
pathogeneses
due to inadequate
of potassium
intake
depletion
are varied
and
in general
of this ion, losses from the gastrointestinal
tract,
are and
excessive losses by way of the urine. Under ordinary, circumstances only very small quantities are lost in the stool and more potassium is ingested in an average diet than is necessary
for growth
even in young individuals.
by the kidneys
into the urine and these organs
in conservation
of potassium
Although excretion
there
as well as in the elimination
is some
of potassium,
understanding
The excess is excreted
play- the most
of the factors
there are still many
unanswered
which
problems.
even an incomplete description of the mechanisms responsible of this cation that gains access to the urine will be helpful some of the problems depletion. quantity proximal
relating
to the pathogenesis
The rate of excretion
of potassium
responsible regulate
the
Nevertheless,
for the quantity in understanding
and consequences
appears
role
of excesses,
of potassium
to be the net result of the
that is filtered at the glomerulus less that which is reabsorbed in the tubule, plus the amount that is secreted into the urine by the more distal
elements of the nephron. The conclusion that a solute which is filtered is also secreted depends on the demonstration that a rate of excretion for that solute can be achieved
which
is in excess of the amount
This has been unequivocally
demonstrated
that was simultaneously
for potassium
filtered.
by several independent
groups of investigators.g-u~‘7g Some suggest that perhaps all of the filtered potassium is reabsorbed and all that gains access to the finally elaborated urine has, in fact, been secreted. The secretory process a mechanism ported
across
referred
the cell membrane
the same and equal direction.
charge,
It is believed
in the distal
as it applies
to as “ion
elements
to potassium appears to operate through in which the potassium ion is trans-
exchange,” into
the luminal
presumably
that
sodium,
this particular
of the nephron,
fluid and some is transported
ion exchange
other ion of
in the opposite
probably
transpires
that it may be in part activated
through
the influence of the hormone aldosterone, and that, in a sense, potassium is in a competitive position with hydrogen ions in this exchange for sodium. This competition
between
potassium
and hydrogen
may be viewed as one which is dictated
ions for exchange
in part at least by the relative
with
sodium
availability
of each cation at the exchange site. There are several important features of this ion exchange system with respect to potassium depletion. The first of these is that, if the bulk of potassium the quantity
of potassium
excretion
is dependent
that is secreted
on an exchange
will be dependent,
with sodium,
in the first instance,
on the quantity of sodium that is delivered to the exchange site. Among the factors that affect the amount of salt delivered to this more distal site are the filtered load and the influence of other solutes and drugs that may diminish the reabsorption of sodium in the more proximal segments of the nephron. Second, the factors which regulate the reabsorption of sodium at the exchange site are of critical significance in determining the rate of excretion of potassium. Prominent among these are secretions of the adrenal cortex, predominantly the mineralocorticoid, aldosterone. Third, anything that will affect the availability of hydrogen
ions will have a reciprocal
effect on the rate of excretion
of potassium.
Volume
11
Number 3
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
215
Thus, alkalosis will tend to augment the excretion of potassium, as will the administration of a carbonic anhydrase inhibitor (such as Diamox) which makes fewer hydrogen ions available for exchange with sodium. Anderson and Laragh2 have presented evidence which suggests that the quantity of sodium in the distal tubule is not the sole factor governing the excretion of potassium. Although the kidneys are able to conserve potassium, their efficiency in this regard is considerably less than is the case with sodium. The ingestion of diets which contain small quantities of potassium is accompanied by the urinary excretion of this cation in excess of intake for as long as 8 to 20 or more days, depending on the absolute amount of potassium ingested and the salt intake with I n addition, some small quantity of powhich this is associated.14~15~82~g5~210~243 tassium continues to be excreted in the normal stoo1.63Thus it is apparent why the simple deprivation of potassium will promote a deficit and why these losses may be enhanced if large loads of sodium salts are administered. A very common cause of potassium depletion is loss of gastrointestinal fluids. This can occur with vomiting, fistulous drainage, diarrhea due to small and large bowel disease (including neoplasms) ,225and excessive use of cathartics234 and enemas.67J02 One of the most common of these is vomiting. There are at least three reasons for the development of potassium depletion with vomiting, and an analysis of this problem serves to emphasize certain features of its pathogenesis. First, because of the persistent vomiting, the ingestion and retention of potassium-containing foods and fluids is impaired. Since renal conservation is initially inadequate, a negative balance of potassium supervenes immediately. Second, gastric and small intestinal secretions contain potassium in concentrations that reportedly vary between 5 and 20 mM. per liter and, therefore, there will be a loss from the body which is dependent on the volume of fluid vomited and the concentration of potassium in that vomitus. Last, if the vomitus is acid gastric fluid, metabolic alkalosis will ensue. The primary renal responses to this event include an augmented rate of excretion of potassium in the urine. This is due, presumably, to the relative unavailability of hydrogen ions at the site of the exchange mechanism. The point that bears emphasis is the fact that the intensity of the deficit of potassium is considerably in excess of the quantity actually lost in the vomitus, for the reasons alluded to above. Although not highly efficient, the kidney, when healthy, is able to respond to changes in potassium intake by altering the rate of excretion. In the usual course of events in renal disease, the problem ultimately becomes one of an inability to eliminate potassium excesses which leads to hyperkalemia and the dire consequences associated with it. There are, however, instances of renal disease in which one of the characteristics is an inability to conserve potassium appropriately and there is a potassium deficit and hypokalemia. This is seen most commonly in association with other renal tubular defects and, in particular, with an inability to acidify the urine. It may well be that the inability to provide or transport hydrogen ions into the urine is the basic defect, and the augmented potassium excretion may be a secondary consequence due to the continued reabsorption of sodium at the exchange site. These patients usually have metabolic acidosis, and evidence of glomerular insufficiency may be minor, at least initially. 27.172,1’17
216
WELT,
Although each
it seems
instance
must
with an example
adenoma
there
are potassium-wasting
closely
alkalosis
or other
J. Chron. March.
AND BLYTHE
to make
aldosteronism.
by metabolic
of aldosterone
cortical
that
be examined
of primary
is accompanied secretion
clear
HOLLANDER,
certain
The potassium
adrenal
cortical
from
or carcinoma
C~~~~~~*5.6,20~22,30,36,37,43,45,52.53.64,~30,135,~43,159~171,~76,183,214~238
pertension
found
to have
hypokalemia
in mind and the first steps the loss of potassium is established
inate renal
or other
urine,
be discussed leads
Other
The tassium
other
as being
between
the
diagnosis
in detail
in the section
such
and
on the
this
may
as estimates
If this
for excessive
and related
elim-
for potassium
losses
of a potassium-wasting
presence
of alkalosis
rather
than
examinations,
kidney),
that
potassium
well complicate urinary
and even exploration
depletion
the clinical
picture.
excretion
of aldo-
may be necessary
in order
the problem. manner
in which
chlorothiazide
is not clear.16r It is possible
to the exchange
that
causes
sites by virtue
of interfering In addition,
carbonic
anhydrase
inhibitor
and
may
an increased
it promotes
level in the nephron.
with sodium although
diminish
excretion
the delivery
reabsorption
not potent,
the
availability
of po-
of more sodium at a more
this agent
since this agent
is now commonly
an increased number of patients between primary aldosteronism
used in the management
is a
of hydrogen
ions just enough to favor the secretion of potassium at the exchange site. have some other independent effect that has not as yet been elucidated.
must
uri-
steroid
I61 If one can confidently responsible
of the 24-hour
proximal
event,
that
on the kidney).
reasons
possibility
The
this
hy_
to demonstrate
the use of cortisone
aldosteronism.
to nephropathy
radiologic
to resolve
decide
adrenal with
levels of blood urea nitrogen, and a benign urinalysis certainly renal disease less likely. One must not forget, however (as will
examinations
sterone,
to exclude
with
study
(see the section
for example, and drugs
and primary
acidosis, normal make a primary
be evaluated balance
drugs such as chlorothiazide.
hormones
one must
disorder
itself
via the urine
of potassium,
exogenous
in the
occurs
an adrenal
of the Patients
must
a careful
one must then be certain
nary excretion compounds
include
in this disorder
and is due to increased
hormones
hyperplasia
disorders,
one is not dealing
deficit
and hypertension
or, less commonly,
renal
that
Dis. 1960
It may In any
of hypertension,
will be seen in whom the differential and a complication of chlorothiazide
diagnosis therapy
be made.
COMPOSITIONAL
CHANGES
Potassium deficiency is accompanied by compositional changes in many, but not all, tissues and fluids. These changes are concerned not only with the specific concentrations of potassium itself, but with alterations in concentration of other ions, both mineral and organic, some related and others unrelated to disturbances in acid-base equilibrium, with changes in enzyme activities and concentrations, and with disturbances in composition related to alterations in protein and carbohydrate metabolism. *Henceforth
the
term
primary
aldosteronism
will
refer
to all such
cases.
Volume 11 Number 3
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
217
It is important to make clear what is meant by a deficit or depletion of potassium. Scribner and Burnel1235emphasize the concept of potassium “capacity.” Potassium is stored in cells in relation to protein and glycogen, and the quantity of these two is the major determinant of the potassium “capacity.” Thus, although potassium may be lost from the body in absolute terms, there is no cell deficit in terms of concentration if equivalent quantities of protein or glycogen are likewise dissipated. On the other hand, if the “capacity” is suddenly increased by feeding protein without potassium to an animal who is deficient in both,147J87 there is a prompt development of chemical evidence of potassium deficiency in terms of tissue and serum analyses. The same situation is exemplified by the administration of potent anabolic androgens252s254in situations characterized by protein depletion. For our purposes, then, the term potassium deficit or depletion will be used to imply a loss of potassium in excess of capacity, and in these terms the quantity of potassium per unit of dry tissue solids will be depressed when there is potassium depletion. Serum.-A depressed concentration of potassium in serum is reflective of a body deficit of this ion except in those situations where there is a sudden shift of potassium from the extracellular compartment to cells, such as in familial periodic paralysis, the administration of glucose and insulin, and, occasionally, the exhibition of andrdgens. The level of potassium in serum is not a good predictor of the intensity of the deficit, however, except in a very general way, and, in fact, normal levels of potassium in serum may coexist with significant cell depletion.236,260Scribner and Burnel1236claim that a deficit of 100 to 200 mEq. of potassium is required to reduce the serum level by 1 mEq. per liter when the initial serum concentration is greater than 3 mEq. per liter, and that when the depletion is severe enough to have reduced the serum level to less than 3 mEq. per liter an additional deficit of 200 to 400 mEq. is required to reduce the concentration in serum by 1 mEq. per liter. Huth, Squires, and Elkinton’45 claim that a level of serum potassium of 3 mEq. per liter implies a deficit of 300 to 400 mEq. Thus, although there is a gross relationship between a loss of potassium and its level in serum, the correlation is poor whether the intensity of the deficit is estimated by analysis of muscle tissue236J60or by determination of the total exchangeable potassium utilizing isotopic potassium.89 Schwartz, Cohen, and Wallace231 have examined the electrolyte changes in the whole body, muscle, red cells, and plasma of the rat and found that when there was a 23 per cent decrease in whole-body potassium, there was a 71 per cent decrease in plasma potassium. The factors that are responsible for the large concentration gradients of potassium between the cellular and the extracellular water will not be discussed here. Whatever these forces may be, however, it is clear that a primary loss of potassium from the extracellular fluid is accompanied by partial replacement from intracellular depots. This has been appreciated in a clinical sense for some time, but has been demonstrated experimentally in a more quantitative fashion using the technique of extracorporeal hemodialysis.87*211 Burnell and his colleaguesz3,*4 emphasize the variety of factors other than the absolute magnitude of total body deficit of potassium that may affect the
218
WELT,
serum
concentration
tracellular
HOLLANDER,
of potassium,
fluids.23J4 There
AND
including
is evidence
J. Chron. Dis. March. 1960
BLYTHE
the influence
(which
of the pH of the ex-
will be discussed
later) concerning
reciprocal transfers of hydrogen ions and potassium between the extracellular and cellular fluids when acidosis or alkalosis supervenes. Burnell and his associates have examined
this in relation
tion of potassium tassium,
to its effect on the specific
in serum. They
there is an inverse relation
of potassium
level of the concentra-
claim that at any given level of total body between
po-
the pH and the serum concentration
such that for every rise or fall of 0.1 pH unit, there is, on the average,
a fall or rise of 0.63 mM. of potassium per liter of serum. Welt and co-workers260 examined the relationship between serum potassium and the intensity of potassium depletion in the rat. The experimental design was such as to produce a wide range of potassium depletion accompanied either by metabolic acidosis or alkalosis serum
or by no significant
and muscle
acid-base
potassium
disturbance.
was examined
groups and it was found that the three regression different with respect to slopes or intercepts. The composiGon of potassium concentration
The
individually
of the serum is altered
Muscle
between
lines were not significantly
in other ways when there is a deficit
and is frequently, but not invariably, characterized by a depressed of chloride, an increase in total CC2 content and in pH, and a
modest rise in the pCO2. These alterations will receive in the section dealing with acid-base equilibrium. of muscle
relationship
for each of these three
Composition tissue
anal Acid-Base
in potassium
more detailed compositional
Eqdibrium.--The
depletion
have
attention
received
great
changes
attention.
Since
muscle tissue represents the largest single tissue mass in the body, its changes are highly significant as a reflection of the alterations in total body composition and of the altered extracellular Data
interrelationships
phases of the body from
tissue analyses
that
may
exist
between
the cellular
and
fluids. are most
usefully
expressed
per unit of fat-free
dry solids (FFDS). In these terms the total water of potassium-depleted muscle is essentially constant, intracellular water may- remain the same or diminish, and the extracellular phase tends to expand. of the manner in which a deficit of potassium this cation
per unit of FFDS
lost a quantity timately animals tances
of dry solids
associated. serum
(primarily
This relationship
are made deficient the
is decreased
as well
mal.147,187~188 When such doubly however, there is a dramatic
the
is induced,
protein) is clearly
muscle
the concentration
unless there has been
in both potassium as
39,50.~8.108,123.127,149,186,236 Regardless
with which revealed
potassium
in the studies
and protein, electrolyte
of
simultaneously is so inin which
since in these circum-
concentrations
are
nor-
deficient animals are then repleted with protein, reduction in muscle potassium concentration.
Another observation which almost invariably accompanies muscle potassium depletion is an increase in the content of sodium. Part of this increased quantity of sodium is in an expanded extracellular phase, but part of it appears to reside within the cells as a replacement for the lost potassium. On occasion this replacement of sodium for potassium has been on a one for one basis, but most often the sum of the concentrations of sodium and potassium in potassium-depleted cells reveals a cation “deficit” when compared with control muscle data. The
Volume 11 Number 3
THE CONSEQIJENCES
OF POTASSIUM
DEPLETION
219
relationship between the loss of muscle potassium and its replacement with sodium has received considerable attention, and the ratio of the gain in sodium to the loss of potassium varies considerably but has frequently been found to be approximately 0.6 to 0.7.3~~4*~50~5~~12~~149~~8*~185~1~7~188~236 This increase in sodium in the cells in potassium deficiency is readily exchangeable,i2* for it has been noted that within 60 minutes the distribution of Na24 between plasma and muscle is in the same proportion as total sodium. The rate of accumulation of sodium in cells with potassium depletion varies with time. For example, the initial loss of potassium exceeds the gain in sodium; later, the rate of loss of potassium diminishes and the rate of accumulation of sodium is increased.185 Some studies suggest that the reverse takes place during the phase of repletion. Conway and Hingerty46 reported a delay in the extrusion of sodium, but their data are expressed in a fashion which makes it impossible to tell whether the retained sodium was in cells or in the extracellular phase. However, in other studies48J85 a similar lag has been observed. In still another investigation, 232the potassium concentration had increased by 40.9 mM. and the sodium concentration had decreased by 40.6 mM. per kilogram of intracellular water in 5 hours. In an investigation of the restoration of muscle potassium following nephrectomy and repletion from endogeneous potassium released by catabolic activity, there were ratios of sodium lost to potassium gained of 1.6, 1.2, and 0.87 at 12, 36, and 60 hours, respectively.263 These data certainly imply no lag in the extrusion of sodium from cells when potassium deficits are restored. The identity of the cations which are unaccounted for by sodium and potassium has received considerable attention. One grouplo reported increase in calcium and magnesium. Other reports do not confirm this.50f231Several groups have demonstrated an increased quantity of lysine and arginine in muscle cells in rats,73-76J47but not in dogs. 146Even if these basic amino acids are included, however, a deficit remains. It has been suggested that the other cation is hydrogen ion.48,57An elaboration of this hypothesis is that the replacement of cell potassium with hydrogen ions from the extracellular fluid is responsible for the alkalosis in this latter compartment. In this context, the extracellular alkalosis is not thought to be due primarily to alterations in renal function, although, as discussed in the section on the kidney, aberrant renal function plays a necessary role in its development. In support of this contention is the report48 that repletion with potassium is accompanied by an increased excretion of hydrogen ions at the same time that the extracellular alkalosis is corrected. In addition, there are the observations of Orloff, Kennedy, and Berliner ig3 that the administration of potassium chloride to potassium-depleted, nephrectomized rats promotes a restoration of the extracellular alkalosis to normal. A similar observation was noted254 when a movement of potassium into cells was accelerated with testosterone in a patient with Cushing’s syndrome. Finally, there are data reported by Gardner, MacLachlan, and Berman108 which purport to demonstrate that there is an intracellular acidosis. These investigators partitioned the CO2 between the extracellular and cellular phase and, using certain assumptions,257 calculated that the intracellular pH changed from 6.98 to 6.48 in potassiumdepleted rats.
220
WELT,
In support
HOl.lANDRK,
of this general
AND
hypothesis
J.
RLYTHE:
concerning
the origins
deviations
excellence
of the correlation
from
the potassium depletion. intake is combined with these
circumstances
Others
have
the degree
these
and it may
potassium there are
well be that
a good deal on the manner
the
of induction
of
The best correlations are noted when a low potassium sodium loads in which the chloride content is low. In
significant
found
good correlations
depends
Dis. 1960
of the extracel-
lular alkalosis is the excellent correlation between depletion of muscle and increase in the total COz content of plasma.61~*45~236 In contrast, significant
Chron. ,March,
alkalosis
the same
of potassium
develops
in dogs as well as rats.i49*ir*J*g
level of bicarbonate
depletion
from
in plasma
with
variations
9 to 33 per cent.3g In another
in
study,
a
reduction in muscle potassium of more than increase in bicarbonate.*41 In this investigation
15 per cent was associated with no the intake of sodium was markedly
limited.
of chloride
Furthermore,
of alkalosis,
although
the associated
a low intake
hypochloremia
of chloride.141,231 One group
did, however,
report
stools of potassium-depleted rats,lng which congenital alkalosis and diarrhea.56z107 Other
features
of the composition
validity
of the
hypothesis
cellular
to the
intracellular
that
the
favors
the development
need not be due to a negative excessive
is reminiscent
of muscle transfer
raise
some
patients
doubts
ions
balance
of chloride
of the
of hydrogen
fluid is responsible
losses
about
from
for the alkalosis.
the
For
in
with the
extra-
example,
when the doubly deficient animals are repleted with protein, sodium enters cells, there is a cation “deficit” in the cells, but there is no aIkalosis.147~187~188 In one report cellular
of the relationship
alkalosis
in sodium
between
to the loss of potassium (0.82
If the cation
of hydrogen
deficit is composed
Most of Gardner, intracellular different that
rather
recently
than
and extra-
to 0.75)
there
to 0.24)
there
was no alkalosis
was an extracellular
alkalosis.
ions, there should have been alkalosis
the latter.
and Wood,72 in a study similar to that no significant change in the MacLachlan, and Berman,io8 calculated pH of muscle of potassium-deficient animals. The reasons for the
results
Eckel,
composition
out that when the ratio of the gain
was low (0.3
and when the ratio was higher with the former
intracellular
in the dog, 14git was pointed
in these
Botschner,
two studies
are not
the level of the pCOz of the plasma
and Berman
was higher
CO2 related
to the depth
the chronic
level of pCO?
pH would be reflective
than it should of anesthesia. in these
of the effect
obvious.
in the study
It
is possible,
of Gardner,
have been, owing to an acute If this datum
animals, of acutely
however,
MacLachlan, retention
were not representative
the calculation superimposed
of of
of the intracellular respiratory
acidosis.
By the same token, in one of the series of Eckels, Botschner, and Wood the pCO2 in the normal and potassium-deficient animals were the same and both were low. This may represent the influence of anesthesia that was too light, which allowed acute hyperventilation due to the stimulation of the experimental involved in obtaining specimens. In one series, however, although levels were a little low, they were higher in the potassium-deficient
procedure the pCO2 animals;
yet the calculated intracellular pH was only 0.08 units lower than the normal. Since the crux of this problem is more concerned with the question of whether the pH of the intracellular and extracellular fluids actually change in opposite
“N;lu$yr
‘3’
THE CONSEQUENCES
OF POTASSIIIM
DEPLETION
221
directions rather than with the absolute amount of this change, even this small difference may, nevertheless, be highly significant. The authors are unable to formulate a unifying concept to explain all of the data. It seems clear that potassium depletion is commonly but not invariably accompanied by extracellular alkalosis. The conditions which favor the development of an alkalosis include the availability of sodium in the diet, especially if this is in excess of chloride (i.e., an alkaline-ash diet). The addition of desoxycorticosterone acetate to promote the retention of sodium accelerates the induction of the alkalosis, presumably due to an increased excretion of potassium and/or an increase in the excretion of hydrogen ions. The alkalosis need not be associated with a negative balance of chloride. Severe metabolic alkalosis can be induced if sodium bicarbonate is administered in the presence of potassium depletion; and this complication should be kept in mind when renal acidosis is corrected.@ The extracellular alkalosis of potassium depletion is not corrected with sodium chloride, but it is with potassium salts. Repletion with potassium may be more efficient if KC1 rather than KHCOa is administered.83 The question of whether there is an intracellular acidosis is still unsettled, and new data, preferably with independent techniques, must be obtained to resolve this dilemma. In addition to the influence of potassium depletion on acid-base interrelationships, there are interesting data concerned with the participation of potassium in exchanges across cell membranes in response to primary alterations in pH of the extracellular fluid. The induction of acidosis promotes the accession of potassium to the extracellular phase presumably from cells23~24~“‘~154~*~~~~4g and, perhaps, from bone. 13,L63Respiratory or metabolic alkalosis is accompanied by a depression of the concentration of potassium in serum but not necessarily with a change in the total quantity of potassium in the extracellular compartment 101.154,201 Myocardium.-The majority of the reports on the potassium content of heart muscle of depleted animals implies that this tissue shares the depletion, but to a lesser extent than skeletal muscle.60~128~146~*74~1~2 One group228 reports only negligible changes in myocardial potassium content and still anotherz68 that there was no change at all. The difference in the responses of the two tissues is illustrated in the following data146: whereas skeletal muscle potassium fell from 37.8 to 26.5 mM., myocardial potassium changed from 41.1 to 37.6 mM. per 100 Gm. of fat-free dry solids. One factor that might tend to mask or minimize a change would be the relatively large quantity of blood that remains in myocardial tissue compared with skeletal muscle. On the other hand, the different response may well be related to one or more qualities of myocardial tissue which distinguish it from skeletal muscle. It is interesting to note in this regard that the smooth muscle of the virgin rat uterus also shares the deficit of potassium to a lesser extent than skeletal muscle .*@ Whereas skeletal muscle potassium changed from 46.3 to 26.6 mM., the uterus muscle changed from 41.0 to 33.3 mM. per 100 Gm. of fat-free dry solids. Perhaps nonstriated muscle has some quality which permits the cells to retain their stores of potassium more efficiently. Liver.-The potassium content of the liver appears to be quite stable, and many investigators have reported no change despite significant total body
222
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March. 1960
deficits.60*65~127~‘74~187 Only one group268 claimed a 30 per cent decrease in liver potassium when desoxycorticosterone was administered to rats, but no actual data are presented in that report. In a study of the free amino acid patterns of tissues during potassium depletion, Iacobellis, Muntwyler, and Dodgeni47 report in addition that, unlike skeletal muscle and kidney, the liver does not share the alterations in the amino acid content that accompanies potassium depletion. These data do not exclude the fact that potassium does enter many interactions between liver tissue and its environment. For example, Darrow and Engels found significant reductions in liver potassium associated with an increase in sodium and chloride when animals were subjected to hemorrhagic shock. Joyner and colleagues152 and Hickam, Wilson, and FrayseP found an increase in hepatic vein potassium in dogs and men with hyperventilation and respiratory alkalosis. The lack of a change in potassium content of the liver when a significant deficit of body potassium has been induced could represent the consequence of losses of organic material along with the potassium, so that an absolute deficit is not reflected when an aliquot of tissue is examined. One argument against this suggestion, however, is the observation of Dodgen and MuntwyleP that the liver glycogen of potassium-deficient animals is actually increased. This question could be resolved by analysis of the entire liver potassium and nitrogen content in control and potassium-depleted animals. Erythrocyte.-since mammalian erythrocytes (except for those of the cat and dog and certain sheep) resemble other cells in that they contain high concentrations of potassium and low levels of sodium, it might be expected that their composition would reflect the changes of potassium depletion in a fashion similar to those of other cells. This they do in a general sense, but there are significant differences and conflicting data. For example, the concentration of potassium in red-cell water appears not to change significantly despite significant deficits as demonstrated by balance techniques in humanP4 or muscle analyses in rats.260 In contrast, Hegnauer 123found reductions in the concentration of potassium in red-cell water in rats. Many observers have reported a decrease in potassium when this is expressed per liter of red cells or per unit of red-cell solids,144,155~231~260 yet this was not confirmed by Schwartz and Relman.234 These conflicts in data may be related, in part, to the degree of depletion, since Schwartz, Cohen, and Wallace231 have pointed out that the erythrocyte sustains the smallest loss when compared with total body, muscle, or plasma deficits of potassium. There is a better correlation between muscle potassium and the concentration of potassium per unit of red-cell solids than with potassium expressed per liter of red cells.260 Kennedy, Winkley, and DunningIs claim an increase concentration of sodium in potassium-depleted red cells in 1 patient. Hove and Herndon’44 make this same claim in potassium-depleted rabbits. However, although the means of the concentrations of sodium in red cells were different in the control and potassium-depleted animals, there was considerable overlap among the data. Thus, neither the serum nor the erythrocyte level of potassium can be satisfactorily correlated with the body deficit of this ion. It has been found in rats, however, that if the plasma level of potassium and its concentration per
;$g;
y
THE CONSEQUENCES
OF POTASSIVM
liter of red cells is used along with the plasma of some significance content
can be developed
of potassiunl.260
potassium (mM.
Muscle
= 8.14
Bruin.-There composition
of
McOuarrie?63
+
3.15
K,
are few and brain
found
tissue
per 100 Gm.
of fat-free
-
+
0.38
EFFECTS
conflicting
the following
As is well summarized been
data
dry solids)
K~ac*
concerning
depletion.
quantity
the alterations
Ziegler,
of brain
muscle
section
0.29
Anderson,
potassium,
potassium
in and
and Hoagland
depletion.
Obviously
on the kidneys.
damage
in several recent reviews,44t175s215s244,245 potassium
functional
appreciated
and structural
clinically
has been recognized
only
derangements
during
in experimental
the
animals
structural
lesions
may
if confirmed,
potassium
cause
would
increased
its adverse
renal effects
where in the body directly
or indirectly
optimal
operation.
Kidney potassium
dependent
Composition
the kidneys
(and
susceptibility
concentration,
data support
presumably
here as else-
processes
assumed
for that
share in whole-body
this contention,
concentration
which are
of potassium
is generally
epithelium)
of
causes
but with certain
of renal tissue is usually
depression of muscle potassium concentrain potassium concentration of tubular urine
for some probably
and in one study
pyelonephritis
deficiency
concentration
Depletion.-It
in potassium
less than half the simultaneous tion’8,‘42~187*1g’; (2) the differences alone will account
although
the renal tubular
The available
(1) the decrease
to chronic
of all the consequences
with vital intracellular
on a particular
renal
They may be wholly or is variable.97~‘64~203 The
in which potassium
unknown,
in Potassium
specifically
deficits.
reservations:
is wholly
it is by interfering
This
although
since 1937.230 The functional
be one of the most serious
depletion.70,175~183,266Th e manner
deple-
of the kidney.
past decade,
as well as the structural changes are primarily tubular. almost wholly reversible,112~135~136J75~*‘3~z34~253 but this which,
equation
of the muscle
ON THE KIDNEY
tion can cause both has
CO?,
in potassium
a diminished
a regression
to prediction
is:
andzStone’33 found no change despite more data are needed in this area. Kidney.-See
CO2 content,
with respect
This equation
223
DEPLETION
small difference
in which kidneys
in total
kidney
were obtained
potassium
during
the peak
of a water diuresis in order to minimize this problem, the renal potassium concentration of potassium-depleted and control rats was almost identica1263; and (3) two other studies,
one in rats+* and one in dogs,ldg have shown
of kidney
potassium
content
potassium
concentrations
(mEq.
per
approximately
unit of fat-free 3.5 per cent
solids)
below
no reduction
despite
controls.
muscle
It is also
noteworthy that, even when a modest decrease in renal potassium has been found, there have been no reciprocal increases in renal sodium concentration.18J87 As with muscle tissue (discussed previously) the potassium-depleted kidneys of the rat appear to contain increased amounts of the amino acids lysine and arginine,‘47 but also as with muscle, this is not so for the dog.146 sents
*K, and COsp represent ConcentratiOns Of Potassium concentration of potassium per liter of red cells.
and carbon
dioxide
in plasma:
Kasc
repre-
224
WELT,
The kidneys
HOLLANDEK,
in experimental
J. Chron. Dis.
AND BLYTHE
potassium
depletion
March,
are enlarged.
1960
It is generally
agreed that solids and water are both increased, either without change in their relative proportions6R~*48~?42 or with a slightly greater proportional increase in water content.**Jg6 Fat appears to remain a constant percentage of total kidney weight.18s242 In one study, free dry solids hyperplasia are
the ratio
was the same
causes
the renal
Renal
Structural
many
studies
of desoxyribonucleic
as that
of pair-fed
Changes
in Experimental
these
Potassium
a pathologic
depleted rats 51,68.93.97,158.175,182,191,194.196,230~242,253 parison of results, however, is hampered of
to fat-
suggesting
that
true
enlargement.62
demonstrating
tions,97~‘64~‘g’~1g6 none
acid-phosphorus
controls,
studies
renal
and
mice
provide
ways:
data
-
There
in potassium-
Interpretation
.164
in several
Depletion.
condition
and com-
(1) with
regarding
four excep-
degree
of po-
tassium
depletion; (2) except where pair-feeding with controls has been emit is difficult to be sure that some abnormalities did not result ployed, 93*158*1g1.242 from nutritiona! deficiencies apart from potassium since potassium-deficient rats eat less well than normal; have
varied
considerably:
(3) techniques
and
(4)
of depletion
localization
and dietary
of lesions
within
constituents nephrons
has
been uncertain because microdissection has been employed in only one study.*gr For these reasons, it is not surprising that the reported pathologic changes have been rather
divergent.
Essentially, location
all
investigators
of the lesions
section
studies
have
agreed
and on the presence
on rats
depleted
on
of tubular
to varying
degrees
(up to 4 weeks), lgl it is now clear that the earliest collecting ducts. These lesions affect all collecting of two types: in several
(1) an intracellular
other The
former
is limited
The
of the granules
entirely
is unknown,
predominantly
dilatation. and
to
tubules
but there
inner
microdis-
for varying
primary
lesions
durations are in the
uniformly
medulla
is histochemical
and
a finding
and hyperplasia the
tubular
From
of large granules,
studies,51J64*‘g4B242 and (2) swelling
epithelium. nature
accumulation
the
are
noted
of the tubular and
papilla.
and electron-
microscopic evidence suggesting that they may be altered mitochondria.r8*T194 The hyperplastic lesion is limited to the outer zone of the medulla and inner cortex,
predominantly
the former.
frequently collecting
causing apparent ducts proximally.
ascending
limb
It involves
of the loop of Henle,
distal convolutions has been described
both
clear
and intercalated
luminal obstruction and consequent This dilatation occasionally extends but otherwise
cells,
dilatation of as high as the
the loops of Henle
and the
convoluted tubule, which are both normal .* The proximal as abnormal in potassium-depleted humans (see below),
is the site in rats, of an inconstant change beginning in its middle third and resembling the hyperplastic lesion of the collecting ducts, with cellular swelling and ultimate cell rupture followed by prolific regenerative hyperplasia. The cellular swelling in the collecting ducts and proximal convolutions is presumably lesion described in other studies,51.g3~‘64~230~24z~253 the “vacuolar” or “hydropic” cells of the *If it is true, as has been suggested by Oli~er’~~~ and Rhodin, z*7 that the intercalated collecting ducts are an extension of normal distal tubular epithelium, it is interesting that the distal convoluted tubule does not participate in the hyperplasia which so intensely affects intercalated cells in the outer medulla.
g;‘$$ \’
THE ,ONSEQUENCES
OF POTASSIUM
DEPLETION
225
and it is noteworthy that the collecting tubules were thought to be the site of a hyperplastic collecting duct lesion in two of the earliest reports on experimental potassium depletion.683164 Although in the microdissection studies demonstrating the collecting duct lesions the rats were alkalotic to varying degrees,rgl identical lesions are seen when rats are given acidifying ion-exchange resins causing potassium depletion with acidosis. 13’ The lesions are also independent of the sodium load.nO In contrast, the severity of the proximal lesion appears to depend on some undefined factors other than the potassium depletion per se, since it is far more striking and consistent in rats made acutely potassium deficient and alkalotic by peritoneal dialysis with sodium bicarbonate 140than in more slowly depleted rats. This may be but one of many situations in which such factors as rate of depletion, intake of other dietary constituents,lg6 and other aspects of wholebody or renal metabolism may condition the precise nature and severity of the renal lesions. The difficulty of defining renal damage as the consequence of a single electrolyte disorder is well illustrated by a recent study14* demonstrating that the proximal tubular lesion associated with phosphate loading is clearly accentuated by potassium deficiency (this proximal lesion is different than that of potassium depletion itself). Although agreeing in principle, this study did not confirm the recent suggestion of Selye and Bajuszz3’ that phosphate loading aggravates the lesions of potassium depletion. Rena1 calcification is not usually present in potassium depletion, but has been noted occasionally (usually calcium casts)g3~158J42and is prominent in the lesion of phosphate loading. r4* Interstitial changes are rarely mentioned, but several recent studies have shown alterations of intertubular ground substance and/or basement membranes in the medulla,51~‘g’~1g4 as well as apparently swollen interstitial cells, perhaps macrophages, which are periodic acid-Schiff positive.51Jg4 Inflammatory cell infiltrations are not characteristic of uncomplicated potassium depletion; neither are visible changes in glomeruli or blood vessels. A variety of enzymatic changes have been reported in the kidneys of potassium-depleted rats. Methods have varied and have involved both wholetissue ana1yses148,242 and histochemistry.5’*1g4J42 In general, however, there is a paucity of interpretable data on this obviously important problem, in that comparatively few enzymes have been studied by more than one group or by more than one technique. Alkaline phosphatase has been found 1ow182~242 and unchanged.51,1g4 Acid phosphatase has been apparently increased in the collecting tubu1es,51,1g4but was unchanged in another study .242Glutaminase activity (units per gram of kidney nitrogen) was increased in potassium-depleted rats as compared to pair-fed controls,148 as it was in the kidneys of potassium-depleted dogs treated with DOCA (but not when dogs were equally depleted of potassium without DOCA).14g It has been reported that nonspecific esterase increased in the proximal tubu1esrg4 but, using somewhat different histochemical methods, other investigators have found it unchanged .51*242 Succinodehydrogenase and the S-nucleotidases have been normal in two studies .51.1g4Other enzymatic findings have included increased activity of carbonic anhydrase (units per gram of nitrogen) ,148 unchanged arginase and amino acid oxidase,148 and variable alterations of lactic dehydrogenase depending on location in the nephron.18* Carbonic
226
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March, 1960
anhydrase in the dog kidney appeared to be depressed when potassium depletion was associated with DOCA treatment and was slightly elevated with potassium depletion on a high bicarbonate intake (without DOCA) but not when chloride replaced the bicarbonate.14g Increases in TPN-diaphorase and opposite changes in DPN-diaphorase have been interpreted as suggesting disturbed respiration and oxidative phosphorylation .lg4The possible significance of the increased glutaminase will be discussed later in relation to urinary acidification. In general, however, both the meaning and the validity of these various reported changes remain uncertain. Since protein depletion may cause depression of renal enzymes,‘48 protein depletion prior to potassium depletion may confuse results, although in this instance2Q the use of pair-fed controls largely negates this objection. Similarly, without more knowledge than presently available regarding the role of many nutritional factors other than potassium, the lack of pair-fed controls51 or an insufficiently detailed description of the control regimenig4 hampers interpretability. Since it is reasonable to suppose that some of the physiologic effects of potassium depletion are mediated through changes in intermediary metabolism, it is interesting that the concentration of pyruvate kinase, which requires potassium as an activator, has been found increased in kidney homogenates of potassium-deficient rats. 62 The increase was limited to the medulla and, when related to DNA-phosphorus, appeared to be a true hypertrophy per cell which more than compensated for the modestly depressed enzyme activity resulting from decreased renal potassium concentration. Although the rat and mouse are the only experimental animals in which the renal structural pathology of potassium depletion has been described, twice in potassium-depleted dogs it has been looked for with entirely negative results.205*240 This is of considerable interest and deserves further investigation.* Renal Structural Changes in Potassium-Depleted Humans.Knowledge regarding renal pathology in potassium-depleted humans comes entirely from three clinical situations, all of which represent potassium depletion, but in association with other metabolic abnormalities: (1) large losses of gastrointestinal fluid, (2) primary aldosteronism, and (3) potassium depletion due to renal potassium wasting of uncertain causation. The latter group35~71~‘67~172~2z7~267 (see Brooks and coauthors, Case No. 320) does not provide much helpful information about the effects of potassium depletion on the kidneys since, although many are probably examples of primary aldosteronism, they may also be one or another type of primary renal disease. Also, the several forms of “renal tubular not acidosis,” while commonly causing potassium deficiency, are obviously generally suitable material for studying the renal consequences of potassium depletion except when abnormalities can be shown to develop with the potassium depletion and to subside following potassium repletion. Perkins, Petersen, and Rileyigg appear to have been the first to ascribe anatomic changes in human kidneys to potassium deficiency. A patient died with almost certain potassium depletion as a result of a long-standing spruelike *Recent unpublished studies are reported to demonstrate renal tubular lesions in potassium-depleted dogs.176*
Volume Number
11 3
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
227
syndrome. The prominent histologic change was a vacuolization of the tubular epithelium which was thought to be mainly but not entirely in the proximal tubule. The vacuoles did not take fat stains, and the authors likened the lesion to that which had been described in potassium-depleted rats. A similar vacuolar or hydropic lesion of the tubular epithelium has now been reported in 16 other potassium-depleted patients, 4 with predominantly gastrointestinal causes of aldosteronism,6,30,37,43,45,55,70,86.'59,238 the potassium deficit, 34,156,213 11 with primary and 1 with gastrointestinal losses but also with chronic glomerulonephritis.35 In 8 of these30~37~55~156~15g~2’3 the lesions were thought to be mainly proximal, the validity of which was established in 4 instances by microdissection of nephrons.37J5 It is of interest, however, that there are 1.5 reports in which this “characteristic” hydropic lesion was apparently absent, 3 with gastrointestinal losses,203J13 9 with primary aldosteronism,6~20-2z~36~52J30~176 and 3 where renal potassium wasting was of uncertain cause. 20~172~267 This suggests that vacuolization is by no means a constant finding, although the significance of its absence in many of these studies is difficult to evaluate because of varying degrees of potassium repletion prior to obtaining kidney tissue. The vacuoles are apparently not Probably they represent glycogen34,45 and only rarely stain for fat. 3ov34,45,156,19g alterations comparable to those which develop in the collecting ducts and proximal tubules in rats,lgl although the evidence currently available suggests that in humans the proximal component is more prominent. Conceivably this may be conditioned by factors other than potassium depletion alone, as already discussed in relation to the rat pathology and perhaps supported by the apparent inconstancy of the lesion in human material. One interesting but wholly speculative possibility is that the vacuolization in proximal tubules is caused or aggravated by partial obstruction of nephrons due to collecting duct lesions such as are found in rats.lgl This suggestion stems from a note by Kulka, Pearson, and RobbinsrGo indicating the production of very similar-appearing proximal vacuolar lesions by ureteral obstruction in rabbits. Whether or not potassium depletion in humans causes collecting duct lesions comparable to those in the rat remains an important unanswered question which can only be settled by microdissection studies involving the entire length of nephrons. In the cases reported by Darmady and Stranack,55 the collecting duct was specifically stated to be normal in 1 instance3? and was not mentioned in the other 3; however, although nephrons were individually dissected, it was almost certainly impossible to study the medullary portion of the collecting system since the material was obtained by renal biopsy. Other structural changes in human kidneys appear to be due primarily associated to such conditions as hypertension aldostein primary ronism,6,20,22,30.37,45,52.70.86,176 h ypertension of uncertain cause,20v267and chronic pyelonephritis. 30,36,15g,176,183,203~213.215 It is noteworthy that a total of 14 potassiumdepleted patients have had complicating pyelonephritis as judged by history, urine cultures, or renal histology, 5,30.36,67.159,176,183.203.213.215.227although in at least 3 of these5~30~227 the pyelonephritis may well have preceded potassium depletion. Relman and SchwartzzL5 have suggested that this complication may be more common in the potassium depletion of primary aldosteronism than that of gastro-
228
WELT,
HOILANDEK,
J. Chron. Dis.
AND IILYTHE
March,
1960
intestinal disorders; however, this is not supported by the current review since 5 of the 14 instances of apparent pyelonephritis were in patients with gastrointestinal
causes
an incidence
of potassium
in this group*
a~dogteronigm.5.30,36~~59.176,1~3,215
been very
rare except
depletion,67J03~213 which
where otherwise
only
available
nephropathy after
information
in humans.
secondary
to
2 to 3 weeks recovery
as little
also
repaired
except
week of rapid
restoration
with
complete
of normal
potassium
be accomplished potassium
potassium
repair
depletion
several
with
renal architecture
collecting
In rats
may occur there
may
of glomeruli.164~253
rubidium
rather
than
in the inner medulla
repletion-in
months
scars in one).
hyalinization
tubules
provided depletion
repletion,164~175,253 although
and occasional
The hyperplastic
have
of potassium
in 2 patients
showed
lesion of collecting
following
as 2 days.n6
with primary changes have
and Schwartz2r3
reversibility
for some “pyelonephritic”
of tubules
can
rapidly
(except
following
sium.t2i5 The granular extremely
biopsies losses
complete
still be some dilatation Prompt
Serial
repletion
and mice, essentially within
regarding
gastrointestinal
potassium
at least as great
explainable.
Reversibility of Structural Changes.-Relman the
represent
as do the 8 cases which were associated A s in rats, glomerular and vascular
potas-
disappears
1 to 2 weeks175*182Jg4 or even in duct lesion,
although
ultimately
for occasional
fibrous scars, did not subside significantly within 1 repletion. I36 Most, but not all, of the enzymes studied
potassium
histochemically
by
days following
Pearse
potassium
structural
abnormalities
reversible.
In conflict
McCance,
and
enlarged
with
another,
comparable
atrophic,
Thus,
the consensus
develop
with
this conclusion,
demonstrating
after
complete hyalinized
study,i3’j
returned
MacPhersonrg4
which with
Parkerg
as long as 7 months
and repletion.
potassium
however,
very
potassium
normal
severe
within
depletion
is the study pathologic
repletion.
glomeruli
the results
to
has been that
and markedly
are
largely
of Fourman,
renal
The kidneys
were qualitatively
7
the renal
condition
were grossly
dilated
tubules.
In
similar
to those
of
Fourman, McCance, and Parker, but far less marked. Although differences in methodology may explain the quantitatively dissimilar findings, it is also possible that
the greater
renal
This
explanation
would,
tion
by Woods
accomplished,
and such
damage
was the
at least,
co-workers266 rats
have
result
be reasonable that,
increased
even
of superimposed long after
susceptibility
Renal Physiology in Potassium Depletion.Urinary concentrating power: There are many which
have
been
reported
in potassium
pyelonephritis.
in view of the recent
depletion,
potassium
to renal alterations the most
demonstrarepletion
is
infection. in renal
profound
function and con-
sistent of which is an impairment of the urinary concentrating mechanism. The earliest indication that this might be so derives from the studies of Loeb and associatess51z05 and from those of Mulinos, Spingern, and Lojkinrs4 demonstrating polydipsia and polyuria in dogs treated with DOCA. The maximum achievable urinary specific gravity was impaired’s4*205 and although the degree of polydipsia -____ *The very interesting reports of gastrointestinal disorders without documented potassium depletion but with pathologic renal condition resembling that seen in potassium depletion have not been included in this review since they can only provide a highly inferential form of evidence. They have been extenSiVely reviewed by Relman and Schwartz 213,215and by Coon and Johnson.44 tRubidium will also prevent renal structural changes in potassium-depleted rats.‘*
E%E11’
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
229
and polyuria was not significantly diminished when additional potassium was supplied,85 urinary concentrating power was not tested in this circumstance. Furthermore, although the potassium supplement prevented paralysis, the data suggest that it may not have completely prevented potassium depletion. Subsequently, Smith and Lasater *41 demonstrated a markedly increased water turnover in dogs on low potassium intakes ti’thout DOCA, but no data were presented regarding urinary concentrating capacity. Brokaw found similar polydipsia and polyuria in rats on potassium-deficient intakes, but concIuded that this was not due to impaired urinary concentrating power.18 However, it has now been clearly established both in the rat13gand dogm that potassium depletion does impair the renal concentrating mechanism. In rats the magnitude of this impairment appears related to the degree of potassium depletion,i39 and the defect occurs whether the potassium-depleted rats have extracellular alkalosis’3g or acidosis.138 It has recently been demonstrated that urinary concentrating power may be impaired if the excretion of urea is inadequate,8’si62 but this will not explain the results in potassium depletion, since some of the rats were pair fed with controls, since the rate of total solute excretion was never significantly lower in potassium-depleted than control animals, and since (in the one group in which it was examined) the rate of excretion of urea by potassiumdepleted rats was not depressed. 13g In dogs, maximum urinary osmolality is significantly depressed whether or not the potassium depletion is associated with administration of DOCA. ii2 It is not clear that the potassium-depleted dogs consumed as much food as controls, and the rate of solute excretion during testing was considerably lower for the DOCA-treated potassium-deficient dogs than for controls; hence, the possibility of inadequate excretion of urea mentioned above must be considered. However, this study”* also included measurement of the maximum negative free-water clearance (Tmc nzo) during mannitol diuresis, and, as this parameter was also significantly diminished, the explanation involving urea is unlikely. 16*Thus, the conclusion that potassium depletion impairs urinary concentrating power in experimental animals seems well established and is in agreement with other reported studies of this problemr75s2r8except for Brokaw’s,18 the results of which may have been influenced by methodologic problems as discussed elsewhere.13g In humans, a similar defect in the urinary concentrating mechanism has been the most prominent and consistent abnormality of renal function noted in association with potassium depletion. Thus, there are 33 instances of definite potassium deficiency due either to gastrointestinal losses or to primary aldosteronism in which maximum urinary concentration was specifically tested ,5~6,20~22~30~37~43~45~52~53~69~'~~86~124~~30~~35~143~159,~71,176,2~3,213,~34,238 and in all but 2 cases53r86concentrating power was clearly impaired. In an additional 7 cases with potassium depletion of uncertain causation, the maximum achievable urinary concentration was also subnormal.20~71J67*172~227~246,*6r In the vast majority of all of these cases the maximum urinary specific gravity was less than 1.015. This case material also demonstrates that, as in experimental animals, the concentrating defect is not related to extracellular acid-base status or to high levels of mineralocorticoid.
230
WELT,
Currently
available
of how often
the
data
renal
potassium repletion and this is also true
HOLLANDER,
do not provide
concentrating
In addition,
there
power, but the longest for most it is less than
only
3 case
reports
had chronic initial
showing
following
pyelonephritis
only 255 months the
are 13 instances
power
is completely
occurring from cure of primary
concentrating months and are
an answer to the important
defect
question
reparable.
In rats,
restores normal urinary concentrating ability rapidly136**75 (or nearly so) for the dog. I” Among human cases, there are
8 examples of complete reparability potassium repletion and/or surgical
centrating
J. Chron. Dis. March, 1960
AND BLYTHE
essentially
in addition
been
period
no improvement however,
to potassium
removal
restoration
of urinary
in this group
is only
~21,22,43,45,52.69.130,172.203,213,238
repletion; of an adrenal
impairment
is uncertain.5 ft has previously
partial
follow-up 6 months
potassium
after surgical
concentrating
demonstrating
1% to 15 months following aldosteronism.6~70~‘~4~~35~143~~34
was slight
in urinary 1 of
the
depletion,r76 adenoma,37
12
There
con-
patients
1 was tested
and in the third
and the duration
of follow-up
suggested lgl that the urinary concentrating defect of the lesions which have been demonstrated in
may in some way be the result the collecting
tubules.
This
is a reasonable
hypothesis
since it is now recognized
that the hyperosmotic concentration of urine is established in the collecting ducts.n6e264 However, the loops of Henle and the distal convoluted tubules are also importantly retically, several
involved
potassium ways:
in the renal concentrating
depletion
could
(1) by interfering
impair
process12J16,264 so that,
urinary
with the hyperosmotic
concentrating reabsorption
theo-
power
of sodium
in and
the counter current multiplier system in the loops of Henle, since together they apparently create the high osmotic concentrations which are established in the interstitial final
fluid of the medulla
abstraction
reabsorption established
of water
water
is largely
between
second
centrating
reabsorption
through
possibility in
to be responsible
ducts;
(2)
by
(isosmotic)
urine distal
the wall of the collecting
has been
reasonably
potassium-depleted
urine in the initial
the early
are thought
collecting
the first and third of these possibilities
defect
hypotonic
the
for the
impairing
water
in the distal convoluted tubule where isotonicity is normally by water transfer out of an initially hypotonic fluid; and (3)
impairing The
and which
from
further tubulen7
portion
along
excluded rats
since
of the distal
in the distal
also suggests
that
The choice
and remains as the cause such
convoluted
rats
unresolved. of the con-
have
tubule
convolution.*
The
hyperosmotic
sodium
in the terminal segment of the ascending
is not impaired
ducts.
reby
normally
and normal
hypotonicity
in
reabsorption
limb of the loop of Henle,
but it does not indicate more than that regarding the functional state of the countercurrent multiplier system. Manitius and colleagues’73 have compared the tonicity of deep medullary tissues in normal and potassium-depleted rats but obtained data which do not clearly exclude either the first or the third of the above theoretic explanations for the urinary concentrating impairment. Further investigation is certainly indicated and, as already discussed, the collecting tubules in cases of human potassium depletion need careful study. *The potassium
recent
studies
depletion
may
of
Giebisch
inhibit
and
water
Lo~ano”~
reabsorption
present in the
evidence distal
which
tubule.
suggests
that,
in
the
dog.
“N:!%-:r :
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
231
Urinary acidification and bicarbonate excretion: Since very large intakes of sodium bicarbonate produce little or no alkalosis in the absence of potassium depletion,49~“4 the propensity to develop metabolic alkalosis in association with potassium depletion is itself evidence of impaired bicarbonate excretion (or impaired chloride reabsorption). This aberration of tubular function has also been demonstrated in a variety of acute experiments in dogs,‘r3 rats,4g and humans.*~~~~~~~~~~220~221 The corrolary of this is, of course, that in the presence of any tendency toward extracellular alkalosis the kidneys of a potassium-depleted subject excrete urine which is inappropriately acid. Frequently the urinary pH is less than 7.0, which has led to the term “paradoxical aciduria,” but this term might more reasonably be used to imply that acid excretion and bicarbonate reabsorption exceed what is appropriate in relation to the extracellular acid-base status. Many examples of this tubular defect could be cited. Thus, the urinary pH was less than 7.0 despite significant extracellular alkalosis in several experimental studies involving potassium-depleted dogs,n3~180 rats,48,4gJ48and humans.14,82,243,265 In the reported cases of primary aldosteronism the urinary pH has varied between 6.0 and 7.5 and, although probably more alkaline than in other forms of potassium depletion, it is not consistently greater than 7.0, as has been suggested.6gs130It is now generally accepted that, as indicated earlier in the section on pathogenesis, the secretion of potassium and hydrogen ions by the renal tubule is in some manner competitive, and it has therefore been proposedi that the relatively increased excretion of acid by potassium-depleted kidneys is due either to a deficiency of potassium in the renal tubular cells or to what is usually considered to be the corrolary of this, increased availability of hydrogen ions in these cells. This concept is supported by the finding that when slices of rabbit kidney cortex were depleted of potassium and incubated with NaHC03 their final bicarbonate concentration was less than that of slices with normal potassium content3 Thus, reabsorption of sodium by the ion exchange mechanism results in a proportionately larger secretion of hydrogen ions and lesser secretion of potassium. The relatively more alkaline urine in primary aldosteronism is also expected from this hypothesis, since in that condition urinary potassium excretion remains high (more than 25 mEq. per 24 hours) despite serum potassium concentrations of less than 3.0 mEq. per liter and the presumably low levels of intracellular p~~~~~~~~,~~29~37~43~46~~3,70,Y9~99~124~~35,143~171,176,238 This is in distinct con_ trast to the generally low levels of urinary potassium (less than 20 mEq. per 24 hours) seen in patients with gastrointestinal losses as the cause of potassium depletion,67,213.234,261 in human subjects experimentally depleted of potasef_ animals. 48,49,93,149,192,242 The sium,14~15~40~82~g5~210~265 and in potassium-depleted feet of mineraloco’rticoid in augmenting potassium excretion despite potassium depletion has also been noted in dogs.149 Potassium depletion appears to cause an increased excretion of ammonium ion (considered in relation to the almost neutral urinary pH which is usually present). This has been noted in primary aldosteronism,7°~176*z44and an acute increment in ammonium excretion has been observed when DOCA was added to a *It has also been shown zz1that an infusion of potassium into normal dogs inhibits the elevated bicarbonate reabsorption normally associated with an elevation of pco2.
232
WELT,
potassium-deficient se, however,
HOLLANDEK,
AND
J. Chron. Dis. March, 1960
BLYTHE
regimen. 145That it is not a function of mineralocorticoid per by several studies of experimental human potassium
is illustrated
and in 2 patients whose potassium depletion was the result depletion 4ov226*243~265 of gastrointestinal losses. 234 The ca:rse of the increased ammonium excretion is uncertain, but has been ascribed to the increased glutaminase previously discussed.r4* Similar rises in renal glutaminase
have been noted in rats chronically
treated
in which
with
elevated due
Diamox,20g
another
in the presence
to ammonium
of relatively
chloride
in all of these situations the suggestion activity
situation
alkaline
administration.
is the presumed
that intracellular
seems a reasonable
acidosis
urine,
208 Since
increase
ammonium
excretion
and in metabolic the common
in intracellular
is the stimulus
is
acidosis
denominator
acidity
for increased
or pCOn,
glutaminase
one.2og
In addition impairs urinary
to these alterations, it has been claimed that potassium depletion acidification, i. e., that despite the inappropriate acid excretion described, there is actually a limited ability to acidify the urine. There is
already
essentially data
no support
indicate
very
for this in animal
low urinary
with severe acidosis
pH levels
(presumably
experiments in acutely
respiratory,
since
the only
relevant
potassium-depleted
secondary
to weakness
dogs87
of respira-
tory muscles). The concept derives primarily from two studies of experimental potassium depletion in human subjects. Clarke and associates40 produced potassium
depletion
and
then acidosis
that the potassium-depleted and a higher slight:
subject
final urinary
pH
with
ammonium
responded
than did controls.
the rates of fall of urinary
pH appear
chloride.
with a slower However,
almost
They
observed
fall in urinary the differences
identical,
pH were
but the potassium-
depleted subject started at a higher pH (6.4 versus 5.5) ; the minimal urinary pH of the potassium-depleted subject (5.2) was only slightly higher than that of controls
(4.5 to 5). Nonetheless,
by finding ment)
that urinary
potassium
the validity
pH increased
depletion
of these differences
was strengthened
from 4.7 to 5.3 when (in a different
was superimposed
on already
existing
experi-
ammonium
chloride acidosis. On the basis of these observations, plus experiments measuring titratable acidity during an infusion of neutral sodium phosphate, the authors concluded
that potassium
not the maximum gave
ammonium
depletion
rate of hydrogen chloride
ion excretion.
to experimentally
noted a less acid urine and a smaller larger increment
limits maximum
of ammonium
increment
excretion
hydrogen Rubini
ion gradient
but
and coauthors226 also
potassium-depleted in titratable
than with controls.
subjects
acidity,
and
but a much
Qualitatively
similar
finding-s have been reported in 3 patients with primary aldosteronism,5JlJ2*70 but in 3 others urinary acidification was little, if at all, impaired.37J14 Hence, potassium depletion may impose some limitation on maximum hydrogen ion gradient in the urine, but this is not clearly established and there is no evidence of impaired capacity There is some
for total acid excretion. evidence that potassium
depletion
depresses
excretion
of
organic acids. This has been shown in potassium-depleted alkalotic rats83 and in 2 human subjects with potassium depletion and acidosis.*g8 There is some further support for these findings in two other studies of experimental potassium -____ *In rats the largest fraction
of the urinary organic acids is alpha-ketoglutarate;
in man it is citrate.83
THE CONSEQLENC’ES
OF POTASSIUM
DEPLETION
233
depletion in humans.4”,s’” In rats, repletion with potassium bicarbonate is followed by increased excretion of organic acids without change in their plasma level, but interestingly this does not occur when repletion is accomplished with potassium chloride.4’-4g,83 Organic acids were similarly unchanged during repletion of 2 patients with potassium chloride, 234but did increase in 2 others.ls3 The significance of these findings is not yet clear and more studies are needed. Cooke and associates4’,4g have suggested that the organic acids may facilitate chloride conservation by serving as essential anions, allowing the excretion of large quantities of cation without chloride and without rise in urine pH. Other renal functions: It has been suggested17? that potassium depletion may impair renal tubular reabsorption of phosphate, but in the case presented the evidence was not conclusive since there were alternative explanations. None of the very meager evidence from animal studies supports this concept48,4g*g3,21g except for one report which shows an apparent decrease in phosphate Tm. during acute lowering of the serum potassium concentration.‘34 There are three studies of experimental potassium depletion in humans (two alkalotic and one acidotic) during which urinary phosphate excretion rose,14*82,g5but there are no studies of phosphate Tm. in potassium-depleted humans, and the subject remains unresolved. The possibility of aminoaciduria as a result of potassium depletion has not been studied in animals and is only rarely mentioned in relation to potassiumdeficient patients. Denton and associates64 reported 2 instances of aminoaciduria which they related to potassium depletion, but the relationship was not established with certainty. Stanbury and Macaulay248 also reported aminoaciduria in association with potassium depletion, but again the data do not particularly suggest a cause and effect relationship. Urinary aminoacids have been normal in 2 cases of primary aldosteronism.21~22*70 Other findings in relation to renal tubular function in potassium depletion have included: normal glucose reabsorption in dogsn2J78 and presumably in humans since renal glycosuria has not been a feature of reported cases; normal capacity to conserve sodium maximally,6J34~*43 although Mahler and Stanbury”* have described a patient with chronic renal disease and a potassium-wasting tendency in whom intermittent impairment of sodium conservation was thought to be the result of intermittent potassium depletion; and apparently normal conservation of potassium itself, 48.49,67.93,149.157.192,213,234,242 which remains almost maximal even in the face of stimuli (such as acute bicarbonate loading) that normally cause increased potassium excretion.40~49~8* One interesting report suggests that, under some circumstances, urinary potassium excretion may reach a minimum and then increase somewhat with progressive potassium depletion. In 2 hypokalemic, alkalotic dogs on a low potassium, high bicarbonate intake (without DOCA), the average daily urinary potassium excretion rose progressively from 0.8 mEq. after 1 week to 4.5 mEq. after 4 weeks.*4g The data presented, however do not, indicate whether or not this could have been due to increased catabolism. Changes in the glomerular filtration rate (GFR) are not striking in potassium depletion and, since glomeruli are not visibly damaged, such reductions as do
234
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March, 1960
occur are probably best explained by the obstruction of nephrons discussed earlier. Measured as the clearance of inulin (Cm), mannitol, or endogenous creatinine, the GFR was either normal or only mildly depressed in all but 2 patients3’v1” of 16 with primary aldosteronism. 6.20,21,22,3’,43,45,69,70,86,124,130,143,171,176,238 When potassium deficiency is due to gastrointestinal causes there may be a somewhat greater tendency for the GFR to be low, ‘15but even SO it is not severely decreased and in 4 of 8 patients it was only mildly so or normal.*67,213,234,26’ Similarly, the serum level of nonprotein nitrogen, (NPN), urea nitrogen (BUN), or creatinine has been elevated in only 3 of 17 patients with primary aldosteronism and in 5 of 10 patients with gastrointestinal losses.1,67J35,213 In 4 experimentally potassium-depleted humans with negative potassium balances of 113 to ,543 mEq., there were no significant changes in the endogenous creatinine cIearance.96*265 In rats, potassium depletion appeared to cause a slight decrease in the endogenous creatinine clearance,l*‘j but the possibility of simultaneous protein depletion as the explanation was not excluded. The BUN may remain normal in potassiumdepleted rats13*or may increase by more than 100 per cent, as may the NPN.97~242 In dogs, the creatinine clearance may remain constant or may decrease slightly with potassium depletion, 112,180 but again it is not clear that the decreases were not the result of diminished protein intake. In contrast, dogs rapidly depleted of potassium by extracorporeal dialysis, with acidosis (presumably respiratory) and apparently unchanged body water, had 50 per cent reductions in GFR (Cm) without change in effective renal plasma flow (clearance of para-aminohippurateCp~n).*~ This interesting observation cannot be explained by the respiratory acidosis66a132 and did not occur in control studies using the same dialysis procedure but without potassium depletion, which points up a need for further investigation of this and other parameters of renal function in rapidly potassium-depleted animals. During a period of a few weeks to 15 months following surgical cure of primary aldosteronism (and potassium repletion), the GFR occasionally has increased to norma1124J43,171; but more often it has fallen (sometimes only transiently), presumably because of the drop in blood pressure and renal vascular disease.37r69*70J76 The only similar studies on patients with gastrointestina1 causes of potassium depletion are those of Relman and Schwartz213J34which showed increases to normal in 2 cases, increase almost to normal in 1, and very little change in 1 (but there was doubt as to the adequacy of potassium repletion). The clearance of para-aminohippurate is frequently somewhat depressed but this is probably a reflection in potassium-depleted patients, 37,6g,159,171,213,234 of another renal tubular defect, the extraction and secretion of PAH,171J34J51 and may not indicate any reduction in renal plasma flow except where renal vascular disease is also present. A similar explanation presumably accounts for the frequently encountered moderate depression of phenol red (P. S. P.) excretion 34,53,135,213,234 Although it has been suggested that potassium deficiency may cause acute oliguria,120 this has not been a recognized consequence of potassium depletion, *Two of the% patients6’*% had normal or almost normal glomerular sium repletion. but data during depletion are not available.
flltration rates just after potas-
F”‘:E7
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
235
and the evidence in this and one other instance 67strongly suggests that the oliguria was due to causes other than the associated potassium deficiency. Potassium-depleted patients usually have either mild proteinuria or none. The urinary sediment is most commonly unremarkable, but occasionally contains a few red cells, white cells, and/or casts. Relation of Alkalosis to Renal Damage.-One of the important unsolved questions closely related to the renal effects of potassium depletion is the effect of alkalosis on the kidney. As indicated in the section on pathogenesis, extracellular alkalosis is commonly and perhaps invariably accompanied by a potassium deficit; it is therefore entirely possible that the renal impairment which has been partially attributed to alkalosis25~26is in fact the result of potassium depletion (plus undoubted dehydration and sodium depletion in many instances). In the rat there are no lesions associated with potassium depletion and alkalosis that are not also seen when the potassium deficiency is produced in association with acidosis.137 Similarly, there is no evidence that renal structural damage or renal functional impairment is any more striking or of any different type in patients with primary aldosteronism, in all but a few of whom5,22,30,37,62.143 alkalosis has been a prominent feature, than it is in patients with potassium depletion secondary to gastrointestinal causes, in whom alkalosis has usually been minimal or absent. Hence, it is tentatively concluded that alkalosis per se is not damaging to the kidneys, but the matter cannot be settled until and unless severe alkalosis can be produced experimentally without potassium depletion (or with very minimal potassium depletion), which, as shown by Cooke and co-workers,4g is at least difficult. POLYDIPSI.4
The polydipsia commonly associated with potassium depletion may be secondary to the impaired renal concentrating process, but this is not established and there are reasons for believing otherwise. Furthermore, there is uncertainty as to whether the polydipsia associated with primary aldosteronism and with DOCA administration in animals is due to potassium depletion alone or to potassium depletion plus another effect of mineralocorticoid. The latter question is unsettled because, although potassium depletion alone clearly can cause polydipsia,18~g5~1ag~241~242 the polydipsia of dogs treated with DOCA was not ameliorated by potassium chloride supplementation,85 and polydipsia seems to be a considerably more prominent symptom in primary aldosteronism (mentioned specifically in 16 of 25 case reports) than it is in patients with potassium depletion due to gastrointestinal causes (mentioned in only 1 of 9 case reports). Also of interest is 1 patient70 in whom thirst and polyuria sudsided rapidly following surgica1 removal of an adrenal adenoma, although the balance data suggest that 80 per cent or more of the potassium repletion had been accomplished before the operation. On the other hand, it has been reported that administration of DOCA does not cause polydipsia in rats, provided the sodium intake is very low,205one possible explanation for which would be that, as is now known,212*236 little or no potassium depletion develops on such a regimen. It has also been reported that, in contrast to the observations of Ragan and
36
WELT,
HOLLANDER,
AND
J. Chron. Dis. IMarch, 1960
BLYTHE
DOCA-treated potassium-depleted associates205 already mentioned, less polyuric when they are repleted with potassium while DOCA
is continuedr*O;
however,
it is not known
the polydipsia)
subsided
completely,
whether
which
the polyuria
is the
crucial
dogs become
(and presumably
information
needed
to answer
this
question. There that
the
is considerable polydipsia
corticoid the
or not,
result
may
of renal
or 2 after centrating
circumstantial
of potassium
evidence
dificiency,
be a primary
concentrating
effect
depletion, begin
it may
hypothesis
by mineralonot
merely
within
a day
animals are placed on a low-potassium diet, before the renal condefect is marked and possibly before it is even demonstrable*1~~139~24*~*42;
mechanisms the result
than
in 2 of the controls,13g
of a tendency
osmolality;
toward
(3) dogs treated
may
their
(1)
the
aggravated
of potassium
impairment:
(2) the average serum solute concentration mOsm. lower in 3 potassium-depleted rats
ism
supporting
whether
have
suggesting that the polydipsia is not and consequent elevation of serum
with DOCA205 and patients
spontaneous
demonstrated
dehydration
measured cryoscopically was 10 with impaired renal concentrating
urinary
specific
with primary
gravities
maxima,21*22~143 or as noted
which
are
by Stanbury
aldosteron-
clearly
they
below
have
urine
volumes which exceed what could be explained by the concentrating defect alone; (4) as has been observed in two experimentally potassium-depleted humanstY and in several patients with primary aldosteronism, 52,53the thirst may be relatively unrelieved rapidly if any, with
by drinking
after
surgical
improvement
primary
concentrated
urine
An attempt
While
it fails fails
imposed EFFECTS
very
in renal
concentrating
(maximum
urinary to prove
and before
power37~45~70~15g; and despite
specific
normal
gravity
primacy
may there
subside is much,
(6) one patient
ability
to produce
of 1.027).
of the polydipsia
by nephrec-
potassium-depleted rats, but spontaneous water ingestion was no greater than that of nephrectomized controls.263
to support
causes
(5) the polydipsia
aldosteronism
53 had polydipsia
has been made
to negate
transiently;
of primary
aldosteronism
tomizing polydipsic after nephrectomy also
except cure
such
the
hypothesis
a hypothesis,
for a diminished
thirst
of a primary since
there may
after
polydipsia,
this
result
well have
been
super-
nephrectomy.
ON THE HEART
The Heart Lesion.-Myocardial lesions have been noted in experimentally produced potassium deficiency in rats,~0~93~‘0*~‘58~‘70~*oO~*30~~55 mice,lc4 pigs,*55 and cats,6o but not in dogs60.240; they have been found in humans dying from conditions associated with potassium deficiency.*15~‘56~‘67~16g~‘gg~B3 The have
essential
been
found,
feature
of the lesions,
is necrosis
of cardiac
common muscle.
to all species Although
in which
they
it has been reported
*The possibility that the polydipsia is actually the cause of the renal concentrating defect’39 has been excluded.‘90 tThese are the only experimentally potassium-depleted humans in whom thirst has been a reported symptom. It is, therefore. interesting that they were more severely depleted than any others with negative potassium balances quite comparable t,o those seen in potassium-depleted patients (839 and 674 mEq.)
Volume 11 Nlml>er 3
THE CONSEQIXNCES
OF l’OTASSIITM
DEPLETION
237
that they occur,p;lu endocardial lesions have generally not been seen in experimental studies; however, the subendocardial areas are apparently the most extensively invo1ved.g3J02J70 The earliest changes consist of swelling and loss of striations of muscle fibers.170 The fibers gradually become necrotic and finally disappear, leaving the containing sarcolemma. Soon afterward or simultaneously, the nuclei begin to shrink and undergo karyolysis or karyorrhexis. Associated with these changes there is an immigration of leukocytes into the areas of necrosis. Early, the leukocytes appear to consist largely of polymorphonuclear neutrophils, but it has been noted that the cells appearing to be predominantly polymorphonuclear neutrophils are actually dark-staining tissue macrophage nuclei, very prominent capillary endothelial nuclei, and only an occasional polymorphonuclear neutrophil. “O Later the tissue macrophages clearly predominate. Whether or not destruction of the existing connective tissue framework with later proliferation of scar tissue occurs in the areas of necrosis is in dispute. The earlier reports indicate that destruction of the framework with subsequent proliferation of connective tissue does occur. French,lo2 however, using more elegant staining techniques, found that although there is collapse of the supporting stroma, no destruction occurs. But he did note some proliferation of vascular endothelium and fibroblasts, indicative of proliferation of connective tissue, even though there was little evidence of formation of new collagen fibers. More recently, McPherson,17o in reassessing the lesions, has proposed that all the changes are secondary to degeneration and death of muscle fibers, phagocytosis of necrotic material, and collapse and condensation of the supporting stroma. As evidence for lack of proliferation of connective tissue, he found no capillary ingrowth, lack of fibroblastic response, and virtual absence of polymorphonuclear neutrophils. He contends, reasonably, that since connective tissue has a very low potassium content, there is no apparent reason why it should be sensitive to potassium lack. It is his impression that if cardiac muscle were capable of complete regeneration, the normal architecture of the heart could be restored, a situation analogous to certain cases of hepatitis in which connective tissue is not damaged and restitution of the normal architecture ensues. Another interesting feature of the lesion is the accumulation of a substance which stains red with Schiff-periodic acid stain in damaged muscle fibers, tissue macrophages, and muscle cells bordering the necrotic foci.102J70 It is thought that the material in the tissue macrophages might represent excess ground substance that is being removed, since prior treatment with diastase does not abolish the staining properties, indicating that the substance is not glycogen. The material in the damaged and ambient muscle fibers is most likely glycogen, since it does not stain after treatment with diastase.l’O Why these myocardial lesions should result from potassium depletion remains unknown. A deficit of body potassium is apparently essential for the production of the lesions, and in rats there is evidence that heart potassium is decreased. Attempts to produce the lesions in dogs, however, have been unsuccessfu160.240 even though in several instances the potassium content of heart has been decreased.6o Reports attesting to a protective effect of pyridoxine256
238
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March, 1960
and a deficiency of thiamine go have not been confirmed.60 Digitalis has been reported to have no effect on the incidence or appearance of the lesions.z** The lesions are more extensive in potassium-depleted rats which are violently exercised.gr It has been stated that the addition of sodium to the diet enhanced the severity of the lesions32 although this effect was attributed to an increased sodium content of the cells, it might simply be the consequence of a more intense deficit of potassium due to the sodium load. Perdue and Phillips’96 claim that a diet with a 20 per cent content of corn oil induces more striking lesions than a diet with only 5 per cent corn oil. They claim there was no difference in skeletal muscle potassium, but the data suggest that there might have been. It should be emphasized that the appearance of the lesions is not unique. Its similarity to the myocarditis associated with diphtheria has been recognized and it has been described as resembling focal myocytolysis,i70 a type of necrosis associated with coronary artery disease.22g Although the myocardial lesions have been reported in humans dying from diseases which are associated with potassium deficiency, for example, diabetic acidosis,*23 steatorrhea,i56J69 and adrenal cortical insufficiency treated with excessive amounts of DOCA,rr5 conclusive evidence for potassium deficiency in these cases is lacking. McAllen 16gstates that in case 1 of his 2 cases, “An electrolyte balance was carried out two weeks before death. This showed a retention of Na and a markedly negative balance for K, the latter being attributable to abnormal loss of potassium in stools.” However, no figures were published. Nevertheless, the clinical situations in all the reports are indicative of potassium deficiency, and the lesions described are in general similar to those reported in experimental potassium deficiency. In several cases, it seems quite likely that coronary artery disease was also present,16gr223 and it may be that in certain of the cases in which massive scarring is reported the changes are secondary to ischemia. Some of the scattered foci of necrosis might also represent the focal myocytolysis associated with coronary artery disease. The Electrocardiogram.-Alterations in the electrocardiogram are a frequent accompaniment of hypokalemia. This is not surprising, since changes in extracellular concentration of potassium have been shown to affect markedly the electrical activity and excitability of the myocardium. r9 Changes in practically every part of the electrocardiogram have been reported, and there is no consistent pattern of hypokalemia.6~1*6,166,216,?46 Th e most commonly observed changes, particularly in man, are depression of the S-T segment, decrease in amplitude and inversion of the T wave, and exaggeration of the U wave. Although prolongation of the Q-T interval has often been reported as an accompaniment of hypokalemia, there is evidence that it is normal in duration and that the apparent prolongation is a resultant of including the U wave in measurement of the Q-T interval.‘26J68~248 Other changes that have been described are increase in the amplitude of the P wave, prolongation of the P-R interval,25g and widening of the QRS coma change usually associated with hyperkalemia. plex, 250~26g Whether these abnormalities are secondary to a decreased extracellular concentration of potassium, a decreased intracellular concentration, or a change in the ratio between the two is not definitely known. These questions have
E%zr‘3’
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
239
remained unanswered largely because of the difficulty in measuring intramyocardial potassium in preparations suitable for recording electrocardiograms. Information which is appropriate, however, has been obtained about the correlation of the electrocardiogram with extracellular and intracellular concentrations of potassium. Schwartz, Levine, and Relma@ analyzed the relationship of the electrocardiographic changes to serum concentration of potassium as well as to total body deficit of potassium in humans in whom varying degrees of potassium depletion had resulted from diarrhea or from administration of DOCA, compound F, or acidifying salts. They found that the electrocardiogram revealed evidence of potassium depletion in only one-half their observations. It was often normal with low serum potassium concentrations and was occasionally abnormal with normal serum concentrations. They concluded that the electrocardiogram was not consistently related to either body deficit or serum concentration of potassium. Experiments have also been performed on dogs in which electrocardiographic changes were related to changes in serum concentration of potassium as well as to varying degrees of total body deficit of potassium. Weller and coauthors,25g utilizing hemodialysis, noted that potassium extraction occurred in two phases: a first phase during which there was a rapid decline in serum concentration of potassium and during which potassium was being removed from the extracellular and intracellular compartments, and a second phase in which the serum concentration of potassium remained constant and potassium was, therefore, presumably being removed from the intracellular compartment. Changes in the electrocardiogram observed throughout the experiments were analyzed. Alterations limited to the first phase consisted of increases in the amplitude of the P wave, prolongation of the P-R interval, and rounding of the T wave. Changes limited to the second phase, when potassium was presumably being removed from the intracellular compartment, were depression of the S-T segment and widening of the QRS complex. Shifts in the QRS axis and the acceleration of heart rate were observed throughout both phases. Similar changes in the electrocardiogram have been observed in experiments with isolated, perfused turtle and dog hearts when the perfusate was potassium free.28 Another line of investigation which has yielded pertinent data is exemplified by the studies of Grob, Johns, and Liljestrand. While studying the movement of potassium in and out of muscle of normal subjectsug and patients with familial periodic paralysis, li8 they recorded ECGs following manipulations which produced hypokalemia by effecting transfer of extracellular potassium into muscle cells. When the arterial concentration of potassium had been decreased below 3.3 mEq. per liter, they noticed in both groups a positive after-potential on the falling limb of the T wave (U wave) as well as slight prolongation of the P-R, QRS, and Q-T intervals and lowering of the T wave. Qualitatively the changes in the electrocardiogram found in these various experiments are quite similar, but the underlying common denominator is not evident. It should be re-emphasized that it is not reasonable to equate derived changes in intracellular potassium or changes in muscle potassium with what
240
WELT,
HOLLANDER,
AND BLYTHE
J. Chum. Dis. March, 1960
is happening in the heart and, until the electrocardiogram can be compared with samples of intramyocardial and extracellular potassium simultaneously obtained, the exact relationship among the three will probably remain unknown. The practical aspect of these considerations is that, at present, the electrocardiogram cannot be relied upon as an indicator of potassium deficiencyeither extracellular or intracellular-for the reasons previously mentioned and also because of other accompanying derangements in extracellular ionic composition which affect the electrocardiogram. Nevertheless, when electrocardiographic patterns consistent with hypokalemia are observed in patients, the presence of potassium deficiency should be verified or excluded by more reliable means. In addition, the electrocardiogram is useful in the therapy of potassium depletion to assist in avoiding the development of hyperkalemia. Arr/zytythmius.-Disturbance in heart rhythm is another of the consequences of the increased excitability of cardiac muscle that results from potassium depletion. The most common accompanying arrhythmias are auricular and ventricular extrasystoles which may or may not be coupled. Auricular tachycardia and auricular flutter have occasionally been observed also.’ It has been in the area of the interrelationship of potassium and digitalis, however, that potassium depletion as a cause for arrhythmias has received the most attention. For many years potassium salts have been used extensively to abolish arrhythmias resulting from exhibition of excessive digitalis and where there has been no evidence of potassium deficiency. Formerly, opinion was that the efficacy of potassium in restoring normal rhythm was due to a pharmacologic effect of reducing myocardial excitability. Since it has been found that toxic doses of digitalis compounds may reduce myocardial concentration of potassium,42f125 it has been suggested that the administration of potassium salts may result in restitution of myocardial potassium to normal. 165 Recently, attention has been called to paroxysmal auricular tachycardia with block’66 as being a particularly common resultant of imbalance between digitalis and potassium. Heart FuiZure.-Signs and symptoms suggestive of congestive heart failure have been observed in several studies of potassium depletion in rats 31,200,242; however, no objective measurements indicative of heart failure have been made. Because of the complexity of the clinical situations in which potassium depletion is usually found in man, it is difficult to ascribe the presence of heart failure to potassium depletion. There have been several reports’03~‘06 of cardiovascular abnormalities including congestive heart failure, occurring in the presence of hypokalemia, which disappeared following the administration of potassium. EFFECT
ON BLOOD PRESSUKE
Lowering of the blood pressure has apparently been produced by potassium by unilateral deprivation in normal ratslo and in rats made hypertensivelO nephrectomy plus the placing of a ligature on the remaining kidney. Recently, it has been found the aortic wall content of potassium is higher in rats made hypertensive by this method than in normal rats and that potassium deprivation leads to a decrease in the potassium content of aortic wall in hypertensive rats as well as in normal rats.101 This has led to speculation that arterial tone is
11 3
Vrhme Number
THE
regulated
(‘ONSECJIEN(‘ES
by concentration
OF
I’OTASSII’M
of potassium
in the arterial
the efficacy of potassium deprivation in lowering PererarY* observed that potassium restriction small
but
EFFEC’TS
statistically
ON
significant
decreases
THE GASTROINTESTINAL
Almost
all
investigations
intestine
which,
of congestion
of the
mucosa
and mononuclear ocytes.
In the
of potassium
edema
into its constituent these studies and
depletion
tassium
but not alkalotic.
was segmental,
patches
of small
depletion
annular
and
in the
and dissociation
on several and
of gastric
They
changes
functions
juice
were present
have been amplified
by Perdue
of acetyl-beta-methylcholine rats
but
not in normal
increased
the effect
of po-
deficient
in po-
made
in pH, decrease in sodium
in titratable concentration
rats
is due to a lack of stimuli EFFECTS
and concluded
rather
motility
that
than an inability
results These
injections
in potassium-depleted
the limited
peristaltic
of the smooth
activity
muscle to respond.
ON METABOLISM
Carbohydrate Metabolism.-That are
and Phillips*g7 who found that intestinal
in
of the gastrointestinal
in rats
and an increase
phag-
intestine,
of the pancreas
Cooke33 studied
found an increase
concentration,
large
of gastric juice. In addition, it has been found that potassium depletion in a decrease in the motility247~258 and propulsive abilityi of the intestine. findings
have
thickening
filled with mononuclear
intestine
Edema
Carone
on composition
potassium
species
examination, was found to consist villi engorged with lymphocytes submucosa,
abnormality.
investigated.
tassium
and
in several
lobules were also noted. Why these absent in others is not apparent.
has also been
acidity
and areas
The effect of potassium tract
depletion
intestinal tract, although distention In two studies on rats, quite similar
feature
and Peyer’s
was the outstanding
men produced
pressure.
on microscopic
phagocytes, intervening
blood
explaining
TRACT
were found.15RJ30 A prominent
of the small
wall, thereby
blood pressure. in hypertensive
in resting
revealed no pathologic alterations in the of the bowel has been frequently observed. changes
241
DEPI,ETION
interrelated
is evident
from
potassium in vitro
and
experiments:
carbohydrate deposition
metabolism of glycogen
in the liver is accompanied by deposition of potassium84; potassium is essential in the phosphorylation of the adenylic system16f17s153; anaerobic glycolysis is inhibited and aerobic of incubating requires
glycolysis rabbit
potassium
is stimulated
by the addition
of potassium
to medium
brain
s1ices4; and optimal glycogenesis in rat liver slices concentrations higher than that of extracellular fluid in order
to maintain a normal intracellular concentration,lz2 whereas increasing potassium concentration in the medium of incubating rat diaphragm inhibits glycogenesis.2g Potassium
depletion
in rat
liver
slices
leads
to decreased
glucose
uptake,
increased glucose output, and increased glucose formation from pyruvate, as well as decreased glycogenesis .iz2 These phenomena are similar to those found in diabetic rat liver slices and have led to the speculation that the deranged metabolism of the diabetic rat liver might be due to potassium depletion; however, potassium concentration in diabetic rat liver has been found to be normal.‘22
242
WELT,
HOLLANDER,
AND BLYTHE
J. Chron. Dis. March, 1960
Potassium depletion has been shown to influence carbohydrate metabolism in animal experiments and clinical studies; however, all the findings are not consistent with those of in vitro experiments. Reduced glucose tolerance has been observed in man78 and rat.105J10Both postprandial”0 and fasting’05 liver glycogen concentrations have been found to be higher than control values in rats, a finding perhaps conflicting with the liver-slice experiments of Hastings and co-workers.n2 In the former experiments, however, there was evidence to suggest increased adrenal cortical activity which could have increased gluconeogenesis and resulted in increased liver glycogen. Liver glycogen was practically absent in rats deprived of potassium for 90 to 120 days.“O This was thought to have resulted from blocked glycogenesis due to cumulative potassium loss; however, starvation might have been the causative factor of the low liver glycogen content. Protein Metabolism.-Failure to grow is a hallmark of chronic potassium deprivation and, indeed, was one of the earliest demonstrated effects of potassium depletion. Part of the growth retardation is no doubt the result of poor dietary intake secondary to anorexia associated with potassium deprivation, but in several experiments growth failure has been shown to be a specific effect of potassium depletion.18~93J3gJ58It is not known whether this resulted specifically from disturbed protein metabolism. It has been demonstrated, however, that nitrogen balance is less positive in potassium-depleted rats than in control rats, even though nitrogen intake in the two groups is not significantly different.rs8 Growth failure is therefore due, in part at least, to derangement in protein metabolism related specifically to lack of potassium. It is not known whether the lessened positivity of nitrogen balance is the result of decreased absorption of nitrogen from the gastrointestinal tract or increased urinary nitrogen excretion secondary to either decreased anabolism or increased catabolism of protein. In man there are no convincing data that potassium depletion promotes nitrogen wasting, but there is evidence that nitrogen retention is more marked in potassium-depleted hypogonadal subjects treated with testosterone when potassium is added to the diet.lzg EFFECTS
ON MUSCLE
Skeletal Muscle Pathology.-Pathologic changes in skeletal muscle have been observed in the rat,41 dog,24o and rabbit.144 It is interesting that out of the many studies on the effects of potassium depletion in the rat, skeletal muscle lesions have been only rarely reported. Cohen, Schwartz, and Wallace4r found extensive involvement of skeletal muscle throughout the body, but particularly in the hind legs. The changes were those of Zenker’s waxy degeneration: the muscle fibers lost their cross striations and then either underwent necrosis or lost their sarcoplasm. Regeneration occurred rapidly after the administration of potassium and consisted largely of reconstitution of muscle fibers by multiplication and production of sarcoplasm on the part of the sarcolemmal cells. Similar changes in muscle have been observed in the dogz40 where muscle paralysis is a more striking feature. In rabbits in which paralysis is also a prominent accompaniment of potassium depletion, “atrophic and streaked musculature of the limbs” has been noted.144
“N::::!3’
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
243
Neuromuscular Function.-Muscle weakness and paralysis occur in various clinical situations in which hypokalemia and/or potassium depletion are present, and they have been produced in experimental studies in dogsz40 and rabbits.144 Neither the incidence nor the magnitude of weakness and paralysis are apparently related to the degree of hypokalemia and/or potassium deficiency per se; in fact, they may be seen in situations in which hyperkalemia is present.64 Although the actual mechanism responsible for the paralysis remains unknown, information which is helpful in understanding why it may be present in some cases of hypokalemia and potassium depletion and absent in others has been advanced in studies of the relationship of muscle function to movement of potassium in and out of muscle in normal subjectsng and in patients with familial periodic paralysis.l18 It was found in normal subjects that maneuvers which increased extracellular potassium concentration and probably decreased or did not affect intracellular concentration, so that the ratio of intracellular to extracellular potassium concentration was probably decreased, were associated with increase in contractility of muscle and ease in depolarization by acetylcholine. These phenomena were attributed to a reduction in resting muscle membrane potential. Conversely, manipulations which probably resulted in an increased intracellular to extracellular potassium concentration ratio were associated with a decrease in ease of depolarization with acetylcholine which was attributed to an increase in the resting membrane potential. Studies on patients with familial periodic paralysis revealed that attacks of weakness which occurred spontaneously or following the administration of food, glucose, or insulin were associated with reduced plasma concentrations and increased muscle uptake of potassium as well as reduction in muscle responsiveness to nerve stimulation and acetylcholine and reduction in propagation of excitation and in contractility. Presumably, in this situation, the unresponsiveness resulted from increase in membrane potential secondary to an increased intracellular to extracellular potassium concentration ratio. On the basis of these studies, the authors postulated that muscle weakness and paralysis occur in familial periodic paralysis when the muscle membrane potential is increased as a result of increase in the ratio of intracellular to extracellular potassium concentrations effected by movement of potassium into muscle cells, and they presume that paralysis results in other situations associated with hypokalemia and/or potassium deficiency when, for various reasons, the ratio is increased. The relatively infrequent occurrence of paralysis in potassium depletion as compared to familial periodic paralysis might be a reflection of the fact that in many situations intracellular and extracellular potassium concentrations are decreased and therefore the ratio between the two tends to remain constant. These postulations are based on the assumption that increased uptake of potassium by muscle cells results in increased intracellular concentration of potassium, an assumption which is not necessarily true. Furthermore, it has been pointed out that the total concentration of potassium inside and/or outside of cells may be of less importance than the levels of ionized potassium.54
244
WELT,
Since
hypokalemia,
muscular
HOLLANDER,
in contrast
irritability,
it might
J.
.4ND BLTTHE
to hypocalcemia,
be anticipated
that
promotes tetany
Chrm. March.
decreased
Dis. 1960
neuro-
would not accompany
potassium depletion. Indeed, it has been pointed out that hypocalcemic tetany may be masked by hypokalemia and appear only when potassium stores are repleted.xO
Tetany
has been
presence77,?06~207~Z?4but for this are not clear. frequently
of ionized
depletion
calcium.
Extracellular
calcium
have
occurred,77J06J24
and
in several
there had been a recent information
regarding
reports
change
alkalosis
effects
reasons
alkalosis
levels
depressed
were
and alkalosis.
to emphasize
tetany
normalg4,206
This explana-
the need for more
of the levels of potassium,
factors,
that
for diminished
and slightly
calcium
on neuromuscular
that has been observed
with potassium
the administration
in the
The
of the cases in which
hypokalemia
other
phenomenon associated
be responsible
in many
and serves
and perhaps
interesting
following
deficiency
the extracellular
may
where
toward
the interrelated
electroencephalograms normal
been present
an oversimplification
pCOZ, pH, magnesium, A related
in potassium
that
potassium
levels of serum
tion is no doubt
however,
It has been suggested
accompanies
concentration
observed,
also in the absence77,g4,150 of hypocalcemia.
concerns
depletion,
calcium,
irritability-. abnormal
with restoration
to
of potassium.gg
EDEMd
The
association
on both clinical
of edema
in experimentally context
as well.
with
potassium
induced Kornberg
deficits
depletionz15
in man
and Endicott
has been commented
and lower animals
158described
and in a
hydrothorax,
ascites,
submucosal intestinal edema, as well as striking separation of the lobules of the pancreas in experimental potassium depletion in the rat. A positive balance of sodium
in excess
of the
negative
balance
many.14~‘5~7g~145~14g~210.212 The discrepancy there
was a negative
balances
of sodium
of increased
augmented
potassium the
excretion
appeared
the
deficit
and
been
space
reported.
early
phase
might
positive Evidence
tissue.3g,50,127~i4g,i85,236 and edema
14.15,88,96~234.256
of repletion, been
by
presented14~15~38~7g,265as well
of muscle
completely have
observed
respectively.
the loss of weight
been
been
and in one instance15
and concomitant
In
some
during
instances
to be followed
by a
corrected.38,234 ascribed
hypoalbuminemia,38,1*1,Zj6
edema disappeared by- an improvement
of acute potassium space was unaltered
has
was more
the edema including
has
and 649 mM.,
chloride
of sodium
during
instances
deficiencies,
fact that the unaccompanied
volume
has likewise
as the potassium
In some tritional
fluid
of 278 mM.
of 1,102
in the calculated
repletion
edema
diuresis
of potassium
and chloride
extracellular
as of an increase The
balance
of potassium
can be quite striking
to coexisting
were
it
not
for
nuthe
with replacement of the potassium deficit in the level of serum albumin. In one study
depletion induced by artificial hemodialysis,204 but the plasma volume was expanded.
the sucrose
It may not be too difficult to offer an explanation for the development of edema in the early phase of repletion with potassium. In this circumstance the entrance of potassium into the cells is accompanied by a release of sodium to the extracellular
fluid. This
can be likened
to the sudden
accession
of an equiva-
\‘olumr
11
xum1m 3
THE (‘ONSEC)I’EN(‘ES
01; I’OT.-\SSII~M DEPLETION
245
lent quantity of sodium from an exogenous source. If appropriate quantities of water are retained with the sodium, there is an isotonic expansion of the extracellular fluid compartment. There is frequently a lag in the dissipation of such an expansion. It is more difficult to understand the retention of sodium in excess of that which replaces potassium in the cells during the development of the depletion. This can hardly be ascribed to an increased secretion of aldosterone, since the evidence suggests that potassium depletion is associated with a diminished excretion of this hormone. 151A depressed glomerular filtration rate is sometimes associated with potassium depletion. Since there is a correlation between the filtered load of sodium and its rate of excretion in the urine, a depressed GFR might be responsible for the retention of sodium in some instances. Although there are unequivocal myocardial lesions and alterations in the ECG during potassium depletion, there is no convincing evidence that these structural and functional abnormalities eventuate in heart failure which, in turn, might promote sodium retention; neither are there obvious disturbances in those factors which are thought to stimulate “volume receptors.“23g It is possible that some specific alteration in the composition and, hence, function of the renal tubular cells is responsible for this sodium retention. A deficiency of potassium in key cells of the renal tubule may well be responsible for a more favorable competitive position of hydrogen ions vis-a-vis potassium for exchange with sodium, but this does not offer an explanation for an increased reabsorption of sodium. The avidity of potassium-depleted renal tubular cells for another cation of equal charge might somehow promote the uptake of sodium from the tubular lumen, but there are no data to support this. In fact, in contrast to other tissues there is no increase in the sodium content of the potassium-depleted kidney. Regardless of the responsible mechanism, it is clear that expansion of the extracellular fluid compartment may occur during the development of potassium depletion and in the early stages of repletion. On the other hand, the authors have not been impressed either with the frequency or the severity of this complication of potassium depletion. It would be wise, nevertheless, to bear this complication in mind whenever an increased volume of extracellular fluid may have particularly deleterious effects. REFERENCES
1.
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WELT,
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AND BLYTHE
J. Chron. Dis. March, 1960
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:t : 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
247
and Potassium Restriction in the Rat: The Total Body Sodium, Nitrogen, Magnesium, and Calcium, J. Clin. Invest. 35:763, 1956. Clarke, E., Evans, B. M., Maclntyre, I., and Mime, M. D.: Acidosis in Experimental Electrolyte Depletion, Clin. SC. 14:421, 1955. Cohen, J., Schwartz, R., and Wallace, W. M.: Lesions of Epiphyseal Cartilage and Skeletal Muscle in Rats on a Diet Deficient in Potassium, A. M. A. Arch. Path. 54:119, 1952. Conn, H. L., Jr.: The Effect of Digitalis and Anoxia on Potassium Transport in the Heart. Correlation With Electrocardiographic Changes, Clin. Res. Proc. 3:111, 1955. Conni5J j y9;jPrimary Aldosteronism, a New Clinical Syndrome, J. Lab. & Clin. Med. Conn, Jr. W., and Johnson, R. D.: Kaliopenic Nephropathy, Am. J. Clin. Nutrition 4:523, 1956. Conn, J. W., and Louis, L. H.: Primary Aldosteronism, a New Clinical Entity, Ann. Int. Med. 44:1, 1956. Conway, E. J., and Hingerty, D.: Relations Between Potassium and Sodium Levels in Mammalian Muscle and Blood Piasma, Biochem. J. 42:372, 1948. Cooke, R. E.: Certain Aspects of the Renal Regulation of Body Composition, Pediatrics 14:567, 1954. Cooke, R. E., Segar, W. E., Cheek, D. B., Coville, F. E., and Darrow, D. C.: The Extrarenal Correction of Alkalosis Associated With Potassium Deficiency, J. Clin. Invest. 31:798, 1952. Cooke, R. E., Segar, W. E., Reed, C., Etzwiler, D. D., Vita, M., Brusilow, S., and Darrow, D. C.: The Role of Potassium in the Prevention of Alkalosis, Am. J. Med. 27:180, 1954. Cotlove, E., Holliday, M. A., Schwartz, R., and Wallace, W. M.: Effects of Electrolyte Depletion and Acid-base Disturbance on Muscle Cations, Am. J. Physiol. 167:665, 1951. Craig, J. M., and Schwartz, R.: Histochemical Study of the Kidney of Rats Fed Diets Deficient in Potassium, A. M. A. Arch. Path. 64:245, 1957. Crane, M. G., Short, G., and Peterson, J. E.: Observations on a Case of Primary Aldosteronism, Am. J. Med. 24:313, 1958. Crane, M. G., Vogel, P. J., and Richland! K. J.: Observations on a Presumptive Case of Primary Aldosteronism, J. Lab. & Chn. Med. 48:1, 1956. Danowski, T. S., and Tarail, R.: Metabolism and Dysfunction of Nervous System Associated With Hyper- and Hypokalemia, Proc. A. Res. Nerv. & Ment. Dis. 32:372, 1953. Darmady, E. M., and Stranack, F.: Microdissection of the Nephron in Disease, Brit. M. Bull. 13:21, 1957. Darrow, D. C.: Congenital Alkalosis With Diarrhea, J. Pediat. 26:519, 1945. Darrow, D. C.: The Role of the Patient in Clinical Research of a Physiological Problem, Yale J. Biol. & Med. 30:1, 1957. Darrow, D. C., Cooke, R. E., and Coville, F. E.: Kidney Electrolyte in Rats With Alkalosis Associated With Potassium Deficiency, Am. J. Physiol. 172:55, 1953. Darrow, D. C., and Engel, F. L.: Liver Water and Electrolytes m Hemorrhagic Shock, Am. J. Physiol. 145:32, 1945-1946. Darrow, D. C., and Miller, H. C.: The Production of Cardiac Lesions by Repeated Injections of Desoxycorticosterone Acetate, J. Clin. Invest. 21:601, 1942. Darrow, D. C., Schwartz, R., Iannucci, J. F., and Coville, F.: The Relation of Serum Bicarbonate Concentration to Muscle Composition, J. Clin. Invest. 27:198, 1948. Davis, R. P.: Personal Communication. Dempsey, E. F., Carroll, E. L., Albright, F., and Henneman, P. H.: A Study of Factors Determining Fecal Electrolyte Excretion, Metabolism 7:108, 1958. Denton, D. A., Synn, V., McDonald, I. R., and Simon, S.: Renal Regulation of the Extracellular Fluid. II. Renal, Physiology in Electrolyte Subtractions, Acta med. scandinav. suppl. 261, 1951. Dodgen, C. L., and Muntwyler, E.: Liver Glycogen in Potassium-deficient Rats Following Carbohydrate and Alanine Administration, With and Without Potassium, Proc. Sot. Exper. Biol. & Med. 98:402, 1958. Dorman, P. J., Sullivan, W. J., and Pitts, R. F.: The Renal Response to Acute Respiratory Acidosis, J. Clin. Invest. 33:82, 1954. Dunning, M. F., and Plum, F.: Potassium Depletion by Enemas, Am. J. Med. 20:789, 1956. Durlacher, S. H., Darrow, D. C., and Winternitz, M. C.: The Effect of Low Potassium Diet and of Desoxycorticosterone Acetate Upon Renal Size, Am. J. Physiol. 136:346, 1942. Dustan, H. P., Corcoran, A. C., and Page, I. H.: Renal Function in Primary Aldosteronism, J. Clin. Invest. 35:1357, 1956. Eales, L., and Linder, G. C.: Primary Aldosteronism. Some Observations on a Case in a Cape Coloured Woman, Quart. J. Med. 25:539, 1956. Earle, D. P., Sherry, S., Eichna, L. W., and Conan, N: J.: Low Potassium Syndrome Due y95yefectlve Renal Tubular Mechamsm for Handlmg Potassmm, Am. J. Med. 11:283,
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WELT,
Eckel,
HOLLANDER,
AND
BLE’THE
J. Chron. Dis. March, 1960
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250 132 133. 134. 135. 136.
137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 1.50. 151. 152. 1.53. 1.54.
1.55. 156. 157. 158. 159. 160. 161. 162.
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AND BLYTHE
J. Chron. Dis. March, 1960
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z%:r ‘: 223. 224. 225. 226.
227. 228.
229.
THE CONSEQLENCES
OF POTASSIUM
DEPLETION
253
on Incidence of Mvocardial Lesions in Potassium Deficient Rats. A.M.A. Arch. Path. 64:228, 1957. _ Report Rodriguez, C. E., Wolfe, A. E., and Bergstrom, V. W.: Hypokalemic Myocarditis: of Two Cases, Am. J. Clin. Path. 20:1050, 1950. Roussak. N. J.: Fatal Hypokalemic Alkalosis With Tetany During Liquorice and P. A. S. Therapy, Brit. M. J. 1:360, 1952. Roy. A. D., and Ellis, H.: Potassium-secreting Tumours of the Large Intestine, Lancet 1:759. 1959. Rubini, Ml E., Blythe, W. B., Herndon, E. G., and Meroney, W. H.: Influence of Potassium Deficiency on Response to an Acidifying Salt, Clin. Res. Proc. 5:193, 19.57 (Abstr.). Russell, G. F. M., Marshall, J , and Stanton, J. B.: Potassium-losing Nephritis: A Clinical Investigation Scot. M. J. 1:122, 1956. St. George., S., Freed, S. C., Rosenman, R. H., and Winderman, S.: Influence of Potassium Deprivation and Adrenalectomy on Potassium Concentration of the Myocardium, Am. J. Physiol. 181:550, 1955. Schle$f;r, M. T., and Reiner, L.: Focal Myocytolysis of the Heart, Am. J. Path. 31:443.
*,-_. 230. 231.
232. 233.
234. 235. 236. 237. 238. 239. 240. 241. 242. 243.
244. 245.
246. 247. 248. 249. 2.50.
251.
Schrader, G. A., Prickett, C. O., and Salmon, W. D.: Symptomatology and Pathology of Potassium and Magnesium Deficiencies m the Rat, J. Nutrition 14:85, 1937. Schwartz, R., Cohen, J., and Wallace, W. M.: Tissue Electrolyte Changes of the Whole Body, Muscle, Erythrocyte and Plasma of Rats on a Potassium Deficient Diet, Am. I. Phvsiol. 172:l. 1953. Schwartz,. k., Cohen, ‘J., and Wallace, W. M.: Distribution of Injected Potassium Salts in Tissues of the Potassium-deficient Rat, Am. T. Phvsiol. 182:39. 1955. Schwartz, W. B., Levine, H. D., and Relman,. A. S.: The-Electrocardiogram in Potassium Depletion. Its Relation to the Total Potassium Deficit and the Serum Concentration, Am. J. Med. 16:395, 1954. Schwartz, W. B., and Relman, A. S.: Metabolic and Renal Studies in Chronic Potassium Depletion Resulting From Overuse of Laxatives, J. Clin. Invest. 32:258, 19.53. Scribner, B. H., and Burnell, J. M.: Interpretation of the Serum Potassium Concentration, Metabolism 5:468, 19.56. Seldin, D. W., Welt, L. G., and Cort, J. H.: The Role of Sodium Salts and Adrenal Steroids in the Production of Hypokalemic Alkalosis, Yale J. Biol. & Med. 29:229, 1956. Selye, H., and Bajusz, E.: Provocation and Prevention of Potassium Deficiency by Various Ions, Proc. Sot. Exper. Biol. & Med. 98:580, 1958. Skanse, B., Moller, F., Gydell, K., Johansson, S., and Wulff, H. B.: Observations on Primary Aldosteronism, Acta med. scandinav. 158:181, 1957. Smith, H. W.: Salt and Water Volume Receptors, Am. J. Med. 23:623, 1957. Smith, S. G., Black-Schaffer, B., and Lasater, T. E.: Potassium Deficiency Syndrome in the Rat and the Dog, Arch. Path. 49:185, 1950. Smith, S. G., and Lasater, T. E.: A Diabetes Insipidus-like Condition Produced in Dogs by a Potassium Deficient Diet, Proc. Sot. Exper. Biol. & Med. 74:427, 1950. Spargo, B.: Kidney Changes in Hypokalemic Alkalosis in the Rat, J. Lab. & Clin. Med. 43:802, 1954. Squires, R. D., and Huth, E. J.: Experimental Potassium Depletion in Normal Human Subjects. I. Relation of Ionic Intakes to the Renal Conservation of Potassium, J. Clin. Invest. 38:1134, 1959. Stanbury, S. W.: Some Aspects of Disordered Renal Tubular Function, in Advances in Internal Medicine, vol. IX, Chicago, 1958, Year Book Publishers, Inc., p. 231. Stanbury, S. W., Gorsenlock. A. H., and Mahler, R. F.: Interrelationships of Potassium Deficiency and Renal Disease, in Muller, A. F., and O’Connor, C. M., editors: An International Symposium on Aldosterone, Boston, 1958, Little, Brown & Company, __ p. 155. Stanbury, S. W., and Macaulay, D.: Defects of Renal Tubular Function in the Nephrotic Syndrome, Quart. J. Med. 26:7, 1957. Streeten, D. H. P., and Vaughn-Williams., E. M.: Loss of Cellular Potassium as Cause of Intestinal Paralysis in Dogs, J. Physiol. 118:149, 1952. Surawicz, B., and Lepeschkin, E. : The Electrocardiographic Pattern of Hypopotassemia With and Without Hypocalcemia, Circulation 8:801, 1953. Swan, R. C., and Pitts, R. F.: Neutralization of Infused Acid by Nephrectomized Dogs, I. Clin. Invest. 34:20.5. 195.5. Sykes, J. F., and Alfredson; B. V.: Studies on the Bovine Electrocardiogram. I. Electrocardiographic Changes in Calves on Low Potassium Rations, Proc. Sot. Exper. Biol. & Med. 43:575, 1940. Taggert, J. V., Silverman, L., and Trayner, E. M.: Influence of Renal Electrolyte Composition on the Tubular Excretion of p-Aminohippurate, Am. J. Physiol. 173:345, 1953.
WELT,
254 252.
2.53. 254. 255. 256. 257 2.55. 259. 260. 261. 262. 263. 264.
265. 266. 267. 268. 269.
HOLLANDER,
AND BLYTHE
J, Chron. March,
Dis. 1960
N. B., Butler, A. M., and MacLachlan, E. A.: The Effect of Testosterone and Allied Compounds on the Mineral! Nitrogen, and Carbohydrate Metabolism of a Girl With Addison’s Disease, J. Chn. Invest. 22:583, 1943. Tauxe, W. N., Wakim, K. G., and Baggenstoss, A. H.: The Renal Lesions in Experimental Deficiency of Potassium, Am. J. Clin. Path. 28:221, 1957. Teabeaut, R., Engel, F. L., and Taylor, H.: Hypokalemic, Hypochloremic Alkalosis in Cushing’s Syndrome. Observations on the Effects of Treatment With Potassium Chloride and Testosterone, J. Clin. Endocrinol. 10:399, 1950. Thomas, R. M., Mylon, E., and Winternitz, M. C.: Myocardial Lesions Resulting From Dietary Deficiency, Yale J. Biol. & Med. 12:34.5, 1940. Vernet, A.! Duckert, A., and Muller, A. F.: Hypokaliemie et oedemes por deperdition intestmale de potassium, Helvet. med. acta 23:490, 1956. Wallace, W. M., and Hastings, A. B.: The Distribution of the Bicarbonate Ion in Mammalian Muscle, J. Biol. Chem. 144:637, 1942. Webster, D. C., Hendricksen, H. W., and Currie, D. J.: Effect of Potassium Deficiency on Intestinal Motility and Gastric Secretion, Ann. Surg. 132:779, 1950. Weller, J. M., Lawn, B., Hoigne, R. V., Wyatt, N. F., Criscitiello, M., Merrill, J. P., and Levine, S. A.: Effects of Acute Removal of Potassium From Dogs. Changes in the Electrocardiogram, Circulation 11:44, 1955. Welt, L. G., Cap, M. P., Gehan, E. A., Winters, R. W., DeWalt, J. L., and Diamond, E. L.: The Prediction of Muscle Potassium From Blood Electrolytes in Potassium Depleted Rats, Tr. A. Am. Physicians 71:250, 1958. Welt, L. G., Hollander, W., Jr., Williams, T. F., and Winters, R. W.: Unpublished Observations. Welt, L. G., and Winters, R. W.: Unpublished Data. Winters, R. W., and Welt, L. G.: Unpublished Observations. Win, H.: The Location of Antidiuretic Action in the Mammalian Kidney, in Heller, H., editor: The Neurohypophysis, London, 1957, Academic Press, Inc., p. 157. Weomersley, R. A., and Darragh, J. H.: Potassium and Sodium Restriction in the Normal Human, J. Clin. Invest. 34:456, 1955. Woods, J. W., Welt, L. G., Hollander, W.. Jr., and Newton, M.: Susceotibility to Esperimental Pyelonephritis During and After Potassium Depletion, J. Clin. Invest. 38:1056, 1959. Wyngaarden, J. B., Keitel, H. G., and Isselbacher, K.: Potassium Depletion and Alkalosis. Their Association With Hypertension and Renal Insufficiency, New England J. Med. 250:597, 1954. Ziegler, M., Anderson, J. A., and McQuarrie, I.: Effects of Desoxycorticosterone Acetate on Water and Electrolyte Content of Brain and Other Tissues, Proc. Sot. Exper. Biol. & Med. 56:242, 1944. Zierler, K. L., and Andres, R.: Movement of Potassium Into Skeletal Muscle During Spontaneous Attack in Family Periodic Paralysis, J. Clin. Invest. 36:730, 19.57. Talbot,
OF POTASSIUM
L. G. WELT, M.D., W. HOLLANDER, JR., M.D.* AND UT. B. BLYTHE, M.D.**
DEPLETION
From she Department
of Medicine,
tine, Universityof North Carolina (Received
for publication
School of Medi-
Dec. 16, 1959)
CHAPELHILL,N.C.
P
OTASSIURl is the major intracellular cation and, as such, must play a key role in the interrelationships between cell structure and function. It is, therefore, not surprising that a deficit of this mineral is accompanied by alterations in cellular activity and anatomic integrity. These disturbances occur in many organs and systems; the structural lesions may be described not only in conventional pathologic terms but in relation to alterations in molecular and ionic composition as well. The functional disturbances are many and vary from gross muscle paralysis to subtle changes in renal tubular activity. In fact, potassium depletion may be manifested by: impaired neuromuscular function that may vary from mild weakness to frank paralysis; alterations in gastric secretions, intestinal dilatation, and ileus; abnormalities of the myocardium with disturbed electrocardiographic patterns, conduction defects, and altered sensitivity to digitalis; abnormal functioning of the kidneys with impaired tubular secretion of para-aminohippurate (PAH), alterations in acidification, an inability to concentrate the urine appropriately, occasional depression in filtration rate, and a probably increased susceptibility to pyelonephritis; a disturbance in the regulation of the volume of the extracellular compartment which must, in part, be mediated via the kidneys; disturbances in acid-base equilibrium which can be related in part to certain features of renal dysfunction, but which may be due in greater measure to the consequences of the cell deficit of potassium and the transfer of hydrogen ions from the extracellular fluid to the cell; polydipsia which may be independent of the renal concentrating defect; disturbances in carbohydrate tolerance and other alterations in intermediary metabolism; changes in neuromuscular irritability which presumably reflect the consequences of disturbances in the usual relationships between calcium, pCOz, and pH; and no doubt many other functional derangements which are yet to be documented and understood. *Markle Scholar in Medical Science. **Fellow, Life Insurance Medical Research Fund. 213
214
WELT,
HOLLANDER,
AND
J. Chron. Dis. March, 1960
BLYTHE
P.4THOGENESIS
The
pathogeneses
due to inadequate
of potassium
intake
depletion
are varied
and
in general
of this ion, losses from the gastrointestinal
tract,
are and
excessive losses by way of the urine. Under ordinary, circumstances only very small quantities are lost in the stool and more potassium is ingested in an average diet than is necessary
for growth
even in young individuals.
by the kidneys
into the urine and these organs
in conservation
of potassium
Although excretion
there
as well as in the elimination
is some
of potassium,
understanding
The excess is excreted
play- the most
of the factors
there are still many
unanswered
which
problems.
even an incomplete description of the mechanisms responsible of this cation that gains access to the urine will be helpful some of the problems depletion. quantity proximal
relating
to the pathogenesis
The rate of excretion
of potassium
responsible regulate
the
Nevertheless,
for the quantity in understanding
and consequences
appears
role
of excesses,
of potassium
to be the net result of the
that is filtered at the glomerulus less that which is reabsorbed in the tubule, plus the amount that is secreted into the urine by the more distal
elements of the nephron. The conclusion that a solute which is filtered is also secreted depends on the demonstration that a rate of excretion for that solute can be achieved
which
is in excess of the amount
This has been unequivocally
demonstrated
that was simultaneously
for potassium
filtered.
by several independent
groups of investigators.g-u~‘7g Some suggest that perhaps all of the filtered potassium is reabsorbed and all that gains access to the finally elaborated urine has, in fact, been secreted. The secretory process a mechanism ported
across
referred
the cell membrane
the same and equal direction.
charge,
It is believed
in the distal
as it applies
to as “ion
elements
to potassium appears to operate through in which the potassium ion is trans-
exchange,” into
the luminal
presumably
that
sodium,
this particular
of the nephron,
fluid and some is transported
ion exchange
other ion of
in the opposite
probably
transpires
that it may be in part activated
through
the influence of the hormone aldosterone, and that, in a sense, potassium is in a competitive position with hydrogen ions in this exchange for sodium. This competition
between
potassium
and hydrogen
may be viewed as one which is dictated
ions for exchange
in part at least by the relative
with
sodium
availability
of each cation at the exchange site. There are several important features of this ion exchange system with respect to potassium depletion. The first of these is that, if the bulk of potassium the quantity
of potassium
excretion
is dependent
that is secreted
on an exchange
will be dependent,
with sodium,
in the first instance,
on the quantity of sodium that is delivered to the exchange site. Among the factors that affect the amount of salt delivered to this more distal site are the filtered load and the influence of other solutes and drugs that may diminish the reabsorption of sodium in the more proximal segments of the nephron. Second, the factors which regulate the reabsorption of sodium at the exchange site are of critical significance in determining the rate of excretion of potassium. Prominent among these are secretions of the adrenal cortex, predominantly the mineralocorticoid, aldosterone. Third, anything that will affect the availability of hydrogen
ions will have a reciprocal
effect on the rate of excretion
of potassium.
Volume
11
Number 3
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
215
Thus, alkalosis will tend to augment the excretion of potassium, as will the administration of a carbonic anhydrase inhibitor (such as Diamox) which makes fewer hydrogen ions available for exchange with sodium. Anderson and Laragh2 have presented evidence which suggests that the quantity of sodium in the distal tubule is not the sole factor governing the excretion of potassium. Although the kidneys are able to conserve potassium, their efficiency in this regard is considerably less than is the case with sodium. The ingestion of diets which contain small quantities of potassium is accompanied by the urinary excretion of this cation in excess of intake for as long as 8 to 20 or more days, depending on the absolute amount of potassium ingested and the salt intake with I n addition, some small quantity of powhich this is associated.14~15~82~g5~210~243 tassium continues to be excreted in the normal stoo1.63Thus it is apparent why the simple deprivation of potassium will promote a deficit and why these losses may be enhanced if large loads of sodium salts are administered. A very common cause of potassium depletion is loss of gastrointestinal fluids. This can occur with vomiting, fistulous drainage, diarrhea due to small and large bowel disease (including neoplasms) ,225and excessive use of cathartics234 and enemas.67J02 One of the most common of these is vomiting. There are at least three reasons for the development of potassium depletion with vomiting, and an analysis of this problem serves to emphasize certain features of its pathogenesis. First, because of the persistent vomiting, the ingestion and retention of potassium-containing foods and fluids is impaired. Since renal conservation is initially inadequate, a negative balance of potassium supervenes immediately. Second, gastric and small intestinal secretions contain potassium in concentrations that reportedly vary between 5 and 20 mM. per liter and, therefore, there will be a loss from the body which is dependent on the volume of fluid vomited and the concentration of potassium in that vomitus. Last, if the vomitus is acid gastric fluid, metabolic alkalosis will ensue. The primary renal responses to this event include an augmented rate of excretion of potassium in the urine. This is due, presumably, to the relative unavailability of hydrogen ions at the site of the exchange mechanism. The point that bears emphasis is the fact that the intensity of the deficit of potassium is considerably in excess of the quantity actually lost in the vomitus, for the reasons alluded to above. Although not highly efficient, the kidney, when healthy, is able to respond to changes in potassium intake by altering the rate of excretion. In the usual course of events in renal disease, the problem ultimately becomes one of an inability to eliminate potassium excesses which leads to hyperkalemia and the dire consequences associated with it. There are, however, instances of renal disease in which one of the characteristics is an inability to conserve potassium appropriately and there is a potassium deficit and hypokalemia. This is seen most commonly in association with other renal tubular defects and, in particular, with an inability to acidify the urine. It may well be that the inability to provide or transport hydrogen ions into the urine is the basic defect, and the augmented potassium excretion may be a secondary consequence due to the continued reabsorption of sodium at the exchange site. These patients usually have metabolic acidosis, and evidence of glomerular insufficiency may be minor, at least initially. 27.172,1’17
216
WELT,
Although each
it seems
instance
must
with an example
adenoma
there
are potassium-wasting
closely
alkalosis
or other
J. Chron. March.
AND BLYTHE
to make
aldosteronism.
by metabolic
of aldosterone
cortical
that
be examined
of primary
is accompanied secretion
clear
HOLLANDER,
certain
The potassium
adrenal
cortical
from
or carcinoma
C~~~~~~*5.6,20~22,30,36,37,43,45,52.53.64,~30,135,~43,159~171,~76,183,214~238
pertension
found
to have
hypokalemia
in mind and the first steps the loss of potassium is established
inate renal
or other
urine,
be discussed leads
Other
The tassium
other
as being
between
the
diagnosis
in detail
in the section
such
and
on the
this
may
as estimates
If this
for excessive
and related
elim-
for potassium
losses
of a potassium-wasting
presence
of alkalosis
rather
than
examinations,
kidney),
that
potassium
well complicate urinary
and even exploration
depletion
the clinical
picture.
excretion
of aldo-
may be necessary
in order
the problem. manner
in which
chlorothiazide
is not clear.16r It is possible
to the exchange
that
causes
sites by virtue
of interfering In addition,
carbonic
anhydrase
inhibitor
and
may
an increased
it promotes
level in the nephron.
with sodium although
diminish
excretion
the delivery
reabsorption
not potent,
the
availability
of po-
of more sodium at a more
this agent
since this agent
is now commonly
an increased number of patients between primary aldosteronism
used in the management
is a
of hydrogen
ions just enough to favor the secretion of potassium at the exchange site. have some other independent effect that has not as yet been elucidated.
must
uri-
steroid
I61 If one can confidently responsible
of the 24-hour
proximal
event,
that
on the kidney).
reasons
possibility
The
this
hy_
to demonstrate
the use of cortisone
aldosteronism.
to nephropathy
radiologic
to resolve
decide
adrenal with
levels of blood urea nitrogen, and a benign urinalysis certainly renal disease less likely. One must not forget, however (as will
examinations
sterone,
to exclude
with
study
(see the section
for example, and drugs
and primary
acidosis, normal make a primary
be evaluated balance
drugs such as chlorothiazide.
hormones
one must
disorder
itself
via the urine
of potassium,
exogenous
in the
occurs
an adrenal
of the Patients
must
a careful
one must then be certain
nary excretion compounds
include
in this disorder
and is due to increased
hormones
hyperplasia
disorders,
one is not dealing
deficit
and hypertension
or, less commonly,
renal
that
Dis. 1960
It may In any
of hypertension,
will be seen in whom the differential and a complication of chlorothiazide
diagnosis therapy
be made.
COMPOSITIONAL
CHANGES
Potassium deficiency is accompanied by compositional changes in many, but not all, tissues and fluids. These changes are concerned not only with the specific concentrations of potassium itself, but with alterations in concentration of other ions, both mineral and organic, some related and others unrelated to disturbances in acid-base equilibrium, with changes in enzyme activities and concentrations, and with disturbances in composition related to alterations in protein and carbohydrate metabolism. *Henceforth
the
term
primary
aldosteronism
will
refer
to all such
cases.
Volume 11 Number 3
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
217
It is important to make clear what is meant by a deficit or depletion of potassium. Scribner and Burnel1235emphasize the concept of potassium “capacity.” Potassium is stored in cells in relation to protein and glycogen, and the quantity of these two is the major determinant of the potassium “capacity.” Thus, although potassium may be lost from the body in absolute terms, there is no cell deficit in terms of concentration if equivalent quantities of protein or glycogen are likewise dissipated. On the other hand, if the “capacity” is suddenly increased by feeding protein without potassium to an animal who is deficient in both,147J87 there is a prompt development of chemical evidence of potassium deficiency in terms of tissue and serum analyses. The same situation is exemplified by the administration of potent anabolic androgens252s254in situations characterized by protein depletion. For our purposes, then, the term potassium deficit or depletion will be used to imply a loss of potassium in excess of capacity, and in these terms the quantity of potassium per unit of dry tissue solids will be depressed when there is potassium depletion. Serum.-A depressed concentration of potassium in serum is reflective of a body deficit of this ion except in those situations where there is a sudden shift of potassium from the extracellular compartment to cells, such as in familial periodic paralysis, the administration of glucose and insulin, and, occasionally, the exhibition of andrdgens. The level of potassium in serum is not a good predictor of the intensity of the deficit, however, except in a very general way, and, in fact, normal levels of potassium in serum may coexist with significant cell depletion.236,260Scribner and Burnel1236claim that a deficit of 100 to 200 mEq. of potassium is required to reduce the serum level by 1 mEq. per liter when the initial serum concentration is greater than 3 mEq. per liter, and that when the depletion is severe enough to have reduced the serum level to less than 3 mEq. per liter an additional deficit of 200 to 400 mEq. is required to reduce the concentration in serum by 1 mEq. per liter. Huth, Squires, and Elkinton’45 claim that a level of serum potassium of 3 mEq. per liter implies a deficit of 300 to 400 mEq. Thus, although there is a gross relationship between a loss of potassium and its level in serum, the correlation is poor whether the intensity of the deficit is estimated by analysis of muscle tissue236J60or by determination of the total exchangeable potassium utilizing isotopic potassium.89 Schwartz, Cohen, and Wallace231 have examined the electrolyte changes in the whole body, muscle, red cells, and plasma of the rat and found that when there was a 23 per cent decrease in whole-body potassium, there was a 71 per cent decrease in plasma potassium. The factors that are responsible for the large concentration gradients of potassium between the cellular and the extracellular water will not be discussed here. Whatever these forces may be, however, it is clear that a primary loss of potassium from the extracellular fluid is accompanied by partial replacement from intracellular depots. This has been appreciated in a clinical sense for some time, but has been demonstrated experimentally in a more quantitative fashion using the technique of extracorporeal hemodialysis.87*211 Burnell and his colleaguesz3,*4 emphasize the variety of factors other than the absolute magnitude of total body deficit of potassium that may affect the
218
WELT,
serum
concentration
tracellular
HOLLANDER,
of potassium,
fluids.23J4 There
AND
including
is evidence
J. Chron. Dis. March. 1960
BLYTHE
the influence
(which
of the pH of the ex-
will be discussed
later) concerning
reciprocal transfers of hydrogen ions and potassium between the extracellular and cellular fluids when acidosis or alkalosis supervenes. Burnell and his associates have examined
this in relation
tion of potassium tassium,
to its effect on the specific
in serum. They
there is an inverse relation
of potassium
level of the concentra-
claim that at any given level of total body between
po-
the pH and the serum concentration
such that for every rise or fall of 0.1 pH unit, there is, on the average,
a fall or rise of 0.63 mM. of potassium per liter of serum. Welt and co-workers260 examined the relationship between serum potassium and the intensity of potassium depletion in the rat. The experimental design was such as to produce a wide range of potassium depletion accompanied either by metabolic acidosis or alkalosis serum
or by no significant
and muscle
acid-base
potassium
disturbance.
was examined
groups and it was found that the three regression different with respect to slopes or intercepts. The composiGon of potassium concentration
The
individually
of the serum is altered
Muscle
between
lines were not significantly
in other ways when there is a deficit
and is frequently, but not invariably, characterized by a depressed of chloride, an increase in total CC2 content and in pH, and a
modest rise in the pCO2. These alterations will receive in the section dealing with acid-base equilibrium. of muscle
relationship
for each of these three
Composition tissue
anal Acid-Base
in potassium
more detailed compositional
Eqdibrium.--The
depletion
have
attention
received
great
changes
attention.
Since
muscle tissue represents the largest single tissue mass in the body, its changes are highly significant as a reflection of the alterations in total body composition and of the altered extracellular Data
interrelationships
phases of the body from
tissue analyses
that
may
exist
between
the cellular
and
fluids. are most
usefully
expressed
per unit of fat-free
dry solids (FFDS). In these terms the total water of potassium-depleted muscle is essentially constant, intracellular water may- remain the same or diminish, and the extracellular phase tends to expand. of the manner in which a deficit of potassium this cation
per unit of FFDS
lost a quantity timately animals tances
of dry solids
associated. serum
(primarily
This relationship
are made deficient the
is decreased
as well
mal.147,187~188 When such doubly however, there is a dramatic
the
is induced,
protein) is clearly
muscle
the concentration
unless there has been
in both potassium as
39,50.~8.108,123.127,149,186,236 Regardless
with which revealed
potassium
in the studies
and protein, electrolyte
of
simultaneously is so inin which
since in these circum-
concentrations
are
nor-
deficient animals are then repleted with protein, reduction in muscle potassium concentration.
Another observation which almost invariably accompanies muscle potassium depletion is an increase in the content of sodium. Part of this increased quantity of sodium is in an expanded extracellular phase, but part of it appears to reside within the cells as a replacement for the lost potassium. On occasion this replacement of sodium for potassium has been on a one for one basis, but most often the sum of the concentrations of sodium and potassium in potassium-depleted cells reveals a cation “deficit” when compared with control muscle data. The
Volume 11 Number 3
THE CONSEQIJENCES
OF POTASSIUM
DEPLETION
219
relationship between the loss of muscle potassium and its replacement with sodium has received considerable attention, and the ratio of the gain in sodium to the loss of potassium varies considerably but has frequently been found to be approximately 0.6 to 0.7.3~~4*~50~5~~12~~149~~8*~185~1~7~188~236 This increase in sodium in the cells in potassium deficiency is readily exchangeable,i2* for it has been noted that within 60 minutes the distribution of Na24 between plasma and muscle is in the same proportion as total sodium. The rate of accumulation of sodium in cells with potassium depletion varies with time. For example, the initial loss of potassium exceeds the gain in sodium; later, the rate of loss of potassium diminishes and the rate of accumulation of sodium is increased.185 Some studies suggest that the reverse takes place during the phase of repletion. Conway and Hingerty46 reported a delay in the extrusion of sodium, but their data are expressed in a fashion which makes it impossible to tell whether the retained sodium was in cells or in the extracellular phase. However, in other studies48J85 a similar lag has been observed. In still another investigation, 232the potassium concentration had increased by 40.9 mM. and the sodium concentration had decreased by 40.6 mM. per kilogram of intracellular water in 5 hours. In an investigation of the restoration of muscle potassium following nephrectomy and repletion from endogeneous potassium released by catabolic activity, there were ratios of sodium lost to potassium gained of 1.6, 1.2, and 0.87 at 12, 36, and 60 hours, respectively.263 These data certainly imply no lag in the extrusion of sodium from cells when potassium deficits are restored. The identity of the cations which are unaccounted for by sodium and potassium has received considerable attention. One grouplo reported increase in calcium and magnesium. Other reports do not confirm this.50f231Several groups have demonstrated an increased quantity of lysine and arginine in muscle cells in rats,73-76J47but not in dogs. 146Even if these basic amino acids are included, however, a deficit remains. It has been suggested that the other cation is hydrogen ion.48,57An elaboration of this hypothesis is that the replacement of cell potassium with hydrogen ions from the extracellular fluid is responsible for the alkalosis in this latter compartment. In this context, the extracellular alkalosis is not thought to be due primarily to alterations in renal function, although, as discussed in the section on the kidney, aberrant renal function plays a necessary role in its development. In support of this contention is the report48 that repletion with potassium is accompanied by an increased excretion of hydrogen ions at the same time that the extracellular alkalosis is corrected. In addition, there are the observations of Orloff, Kennedy, and Berliner ig3 that the administration of potassium chloride to potassium-depleted, nephrectomized rats promotes a restoration of the extracellular alkalosis to normal. A similar observation was noted254 when a movement of potassium into cells was accelerated with testosterone in a patient with Cushing’s syndrome. Finally, there are data reported by Gardner, MacLachlan, and Berman108 which purport to demonstrate that there is an intracellular acidosis. These investigators partitioned the CO2 between the extracellular and cellular phase and, using certain assumptions,257 calculated that the intracellular pH changed from 6.98 to 6.48 in potassiumdepleted rats.
220
WELT,
In support
HOl.lANDRK,
of this general
AND
hypothesis
J.
RLYTHE:
concerning
the origins
deviations
excellence
of the correlation
from
the potassium depletion. intake is combined with these
circumstances
Others
have
the degree
these
and it may
potassium there are
well be that
a good deal on the manner
the
of induction
of
The best correlations are noted when a low potassium sodium loads in which the chloride content is low. In
significant
found
good correlations
depends
Dis. 1960
of the extracel-
lular alkalosis is the excellent correlation between depletion of muscle and increase in the total COz content of plasma.61~*45~236 In contrast, significant
Chron. ,March,
alkalosis
the same
of potassium
develops
in dogs as well as rats.i49*ir*J*g
level of bicarbonate
depletion
from
in plasma
with
variations
9 to 33 per cent.3g In another
in
study,
a
reduction in muscle potassium of more than increase in bicarbonate.*41 In this investigation
15 per cent was associated with no the intake of sodium was markedly
limited.
of chloride
Furthermore,
of alkalosis,
although
the associated
a low intake
hypochloremia
of chloride.141,231 One group
did, however,
report
stools of potassium-depleted rats,lng which congenital alkalosis and diarrhea.56z107 Other
features
of the composition
validity
of the
hypothesis
cellular
to the
intracellular
that
the
favors
the development
need not be due to a negative excessive
is reminiscent
of muscle transfer
raise
some
patients
doubts
ions
balance
of chloride
of the
of hydrogen
fluid is responsible
losses
about
from
for the alkalosis.
the
For
in
with the
extra-
example,
when the doubly deficient animals are repleted with protein, sodium enters cells, there is a cation “deficit” in the cells, but there is no aIkalosis.147~187~188 In one report cellular
of the relationship
alkalosis
in sodium
between
to the loss of potassium (0.82
If the cation
of hydrogen
deficit is composed
Most of Gardner, intracellular different that
rather
recently
than
and extra-
to 0.75)
there
to 0.24)
there
was no alkalosis
was an extracellular
alkalosis.
ions, there should have been alkalosis
the latter.
and Wood,72 in a study similar to that no significant change in the MacLachlan, and Berman,io8 calculated pH of muscle of potassium-deficient animals. The reasons for the
results
Eckel,
composition
out that when the ratio of the gain
was low (0.3
and when the ratio was higher with the former
intracellular
in the dog, 14git was pointed
in these
Botschner,
two studies
are not
the level of the pCOz of the plasma
and Berman
was higher
CO2 related
to the depth
the chronic
level of pCO?
pH would be reflective
than it should of anesthesia. in these
of the effect
obvious.
in the study
It
is possible,
of Gardner,
have been, owing to an acute If this datum
animals, of acutely
however,
MacLachlan, retention
were not representative
the calculation superimposed
of of
of the intracellular respiratory
acidosis.
By the same token, in one of the series of Eckels, Botschner, and Wood the pCO2 in the normal and potassium-deficient animals were the same and both were low. This may represent the influence of anesthesia that was too light, which allowed acute hyperventilation due to the stimulation of the experimental involved in obtaining specimens. In one series, however, although levels were a little low, they were higher in the potassium-deficient
procedure the pCO2 animals;
yet the calculated intracellular pH was only 0.08 units lower than the normal. Since the crux of this problem is more concerned with the question of whether the pH of the intracellular and extracellular fluids actually change in opposite
“N;lu$yr
‘3’
THE CONSEQUENCES
OF POTASSIIIM
DEPLETION
221
directions rather than with the absolute amount of this change, even this small difference may, nevertheless, be highly significant. The authors are unable to formulate a unifying concept to explain all of the data. It seems clear that potassium depletion is commonly but not invariably accompanied by extracellular alkalosis. The conditions which favor the development of an alkalosis include the availability of sodium in the diet, especially if this is in excess of chloride (i.e., an alkaline-ash diet). The addition of desoxycorticosterone acetate to promote the retention of sodium accelerates the induction of the alkalosis, presumably due to an increased excretion of potassium and/or an increase in the excretion of hydrogen ions. The alkalosis need not be associated with a negative balance of chloride. Severe metabolic alkalosis can be induced if sodium bicarbonate is administered in the presence of potassium depletion; and this complication should be kept in mind when renal acidosis is corrected.@ The extracellular alkalosis of potassium depletion is not corrected with sodium chloride, but it is with potassium salts. Repletion with potassium may be more efficient if KC1 rather than KHCOa is administered.83 The question of whether there is an intracellular acidosis is still unsettled, and new data, preferably with independent techniques, must be obtained to resolve this dilemma. In addition to the influence of potassium depletion on acid-base interrelationships, there are interesting data concerned with the participation of potassium in exchanges across cell membranes in response to primary alterations in pH of the extracellular fluid. The induction of acidosis promotes the accession of potassium to the extracellular phase presumably from cells23~24~“‘~154~*~~~~4g and, perhaps, from bone. 13,L63Respiratory or metabolic alkalosis is accompanied by a depression of the concentration of potassium in serum but not necessarily with a change in the total quantity of potassium in the extracellular compartment 101.154,201 Myocardium.-The majority of the reports on the potassium content of heart muscle of depleted animals implies that this tissue shares the depletion, but to a lesser extent than skeletal muscle.60~128~146~*74~1~2 One group228 reports only negligible changes in myocardial potassium content and still anotherz68 that there was no change at all. The difference in the responses of the two tissues is illustrated in the following data146: whereas skeletal muscle potassium fell from 37.8 to 26.5 mM., myocardial potassium changed from 41.1 to 37.6 mM. per 100 Gm. of fat-free dry solids. One factor that might tend to mask or minimize a change would be the relatively large quantity of blood that remains in myocardial tissue compared with skeletal muscle. On the other hand, the different response may well be related to one or more qualities of myocardial tissue which distinguish it from skeletal muscle. It is interesting to note in this regard that the smooth muscle of the virgin rat uterus also shares the deficit of potassium to a lesser extent than skeletal muscle .*@ Whereas skeletal muscle potassium changed from 46.3 to 26.6 mM., the uterus muscle changed from 41.0 to 33.3 mM. per 100 Gm. of fat-free dry solids. Perhaps nonstriated muscle has some quality which permits the cells to retain their stores of potassium more efficiently. Liver.-The potassium content of the liver appears to be quite stable, and many investigators have reported no change despite significant total body
222
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March. 1960
deficits.60*65~127~‘74~187 Only one group268 claimed a 30 per cent decrease in liver potassium when desoxycorticosterone was administered to rats, but no actual data are presented in that report. In a study of the free amino acid patterns of tissues during potassium depletion, Iacobellis, Muntwyler, and Dodgeni47 report in addition that, unlike skeletal muscle and kidney, the liver does not share the alterations in the amino acid content that accompanies potassium depletion. These data do not exclude the fact that potassium does enter many interactions between liver tissue and its environment. For example, Darrow and Engels found significant reductions in liver potassium associated with an increase in sodium and chloride when animals were subjected to hemorrhagic shock. Joyner and colleagues152 and Hickam, Wilson, and FrayseP found an increase in hepatic vein potassium in dogs and men with hyperventilation and respiratory alkalosis. The lack of a change in potassium content of the liver when a significant deficit of body potassium has been induced could represent the consequence of losses of organic material along with the potassium, so that an absolute deficit is not reflected when an aliquot of tissue is examined. One argument against this suggestion, however, is the observation of Dodgen and MuntwyleP that the liver glycogen of potassium-deficient animals is actually increased. This question could be resolved by analysis of the entire liver potassium and nitrogen content in control and potassium-depleted animals. Erythrocyte.-since mammalian erythrocytes (except for those of the cat and dog and certain sheep) resemble other cells in that they contain high concentrations of potassium and low levels of sodium, it might be expected that their composition would reflect the changes of potassium depletion in a fashion similar to those of other cells. This they do in a general sense, but there are significant differences and conflicting data. For example, the concentration of potassium in red-cell water appears not to change significantly despite significant deficits as demonstrated by balance techniques in humanP4 or muscle analyses in rats.260 In contrast, Hegnauer 123found reductions in the concentration of potassium in red-cell water in rats. Many observers have reported a decrease in potassium when this is expressed per liter of red cells or per unit of red-cell solids,144,155~231~260 yet this was not confirmed by Schwartz and Relman.234 These conflicts in data may be related, in part, to the degree of depletion, since Schwartz, Cohen, and Wallace231 have pointed out that the erythrocyte sustains the smallest loss when compared with total body, muscle, or plasma deficits of potassium. There is a better correlation between muscle potassium and the concentration of potassium per unit of red-cell solids than with potassium expressed per liter of red cells.260 Kennedy, Winkley, and DunningIs claim an increase concentration of sodium in potassium-depleted red cells in 1 patient. Hove and Herndon’44 make this same claim in potassium-depleted rabbits. However, although the means of the concentrations of sodium in red cells were different in the control and potassium-depleted animals, there was considerable overlap among the data. Thus, neither the serum nor the erythrocyte level of potassium can be satisfactorily correlated with the body deficit of this ion. It has been found in rats, however, that if the plasma level of potassium and its concentration per
;$g;
y
THE CONSEQUENCES
OF POTASSIVM
liter of red cells is used along with the plasma of some significance content
can be developed
of potassiunl.260
potassium (mM.
Muscle
= 8.14
Bruin.-There composition
of
McOuarrie?63
+
3.15
K,
are few and brain
found
tissue
per 100 Gm.
of fat-free
-
+
0.38
EFFECTS
conflicting
the following
As is well summarized been
data
dry solids)
K~ac*
concerning
depletion.
quantity
the alterations
Ziegler,
of brain
muscle
section
0.29
Anderson,
potassium,
potassium
in and
and Hoagland
depletion.
Obviously
on the kidneys.
damage
in several recent reviews,44t175s215s244,245 potassium
functional
appreciated
and structural
clinically
has been recognized
only
derangements
during
in experimental
the
animals
structural
lesions
may
if confirmed,
potassium
cause
would
increased
its adverse
renal effects
where in the body directly
or indirectly
optimal
operation.
Kidney potassium
dependent
Composition
the kidneys
(and
susceptibility
concentration,
data support
presumably
here as else-
processes
assumed
for that
share in whole-body
this contention,
concentration
which are
of potassium
is generally
epithelium)
of
causes
but with certain
of renal tissue is usually
depression of muscle potassium concentrain potassium concentration of tubular urine
for some probably
and in one study
pyelonephritis
deficiency
concentration
Depletion.-It
in potassium
less than half the simultaneous tion’8,‘42~187*1g’; (2) the differences alone will account
although
the renal tubular
The available
(1) the decrease
to chronic
of all the consequences
with vital intracellular
on a particular
renal
They may be wholly or is variable.97~‘64~203 The
in which potassium
unknown,
in Potassium
specifically
deficits.
reservations:
is wholly
it is by interfering
This
although
since 1937.230 The functional
be one of the most serious
depletion.70,175~183,266Th e manner
deple-
of the kidney.
past decade,
as well as the structural changes are primarily tubular. almost wholly reversible,112~135~136J75~*‘3~z34~253 but this which,
equation
of the muscle
ON THE KIDNEY
tion can cause both has
CO?,
in potassium
a diminished
a regression
to prediction
is:
andzStone’33 found no change despite more data are needed in this area. Kidney.-See
CO2 content,
with respect
This equation
223
DEPLETION
small difference
in which kidneys
in total
kidney
were obtained
potassium
during
the peak
of a water diuresis in order to minimize this problem, the renal potassium concentration of potassium-depleted and control rats was almost identica1263; and (3) two other studies,
one in rats+* and one in dogs,ldg have shown
of kidney
potassium
content
potassium
concentrations
(mEq.
per
approximately
unit of fat-free 3.5 per cent
solids)
below
no reduction
despite
controls.
muscle
It is also
noteworthy that, even when a modest decrease in renal potassium has been found, there have been no reciprocal increases in renal sodium concentration.18J87 As with muscle tissue (discussed previously) the potassium-depleted kidneys of the rat appear to contain increased amounts of the amino acids lysine and arginine,‘47 but also as with muscle, this is not so for the dog.146 sents
*K, and COsp represent ConcentratiOns Of Potassium concentration of potassium per liter of red cells.
and carbon
dioxide
in plasma:
Kasc
repre-
224
WELT,
The kidneys
HOLLANDEK,
in experimental
J. Chron. Dis.
AND BLYTHE
potassium
depletion
March,
are enlarged.
1960
It is generally
agreed that solids and water are both increased, either without change in their relative proportions6R~*48~?42 or with a slightly greater proportional increase in water content.**Jg6 Fat appears to remain a constant percentage of total kidney weight.18s242 In one study, free dry solids hyperplasia are
the ratio
was the same
causes
the renal
Renal
Structural
many
studies
of desoxyribonucleic
as that
of pair-fed
Changes
in Experimental
these
Potassium
a pathologic
depleted rats 51,68.93.97,158.175,182,191,194.196,230~242,253 parison of results, however, is hampered of
to fat-
suggesting
that
true
enlargement.62
demonstrating
tions,97~‘64~‘g’~1g6 none
acid-phosphorus
controls,
studies
renal
and
mice
provide
ways:
data
-
There
in potassium-
Interpretation
.164
in several
Depletion.
condition
and com-
(1) with
regarding
four excep-
degree
of po-
tassium
depletion; (2) except where pair-feeding with controls has been emit is difficult to be sure that some abnormalities did not result ployed, 93*158*1g1.242 from nutritiona! deficiencies apart from potassium since potassium-deficient rats eat less well than normal; have
varied
considerably:
(3) techniques
and
(4)
of depletion
localization
and dietary
of lesions
within
constituents nephrons
has
been uncertain because microdissection has been employed in only one study.*gr For these reasons, it is not surprising that the reported pathologic changes have been rather
divergent.
Essentially, location
all
investigators
of the lesions
section
studies
have
agreed
and on the presence
on rats
depleted
on
of tubular
to varying
degrees
(up to 4 weeks), lgl it is now clear that the earliest collecting ducts. These lesions affect all collecting of two types: in several
(1) an intracellular
other The
former
is limited
The
of the granules
entirely
is unknown,
predominantly
dilatation. and
to
tubules
but there
inner
microdis-
for varying
primary
lesions
durations are in the
uniformly
medulla
is histochemical
and
a finding
and hyperplasia the
tubular
From
of large granules,
studies,51J64*‘g4B242 and (2) swelling
epithelium. nature
accumulation
the
are
noted
of the tubular and
papilla.
and electron-
microscopic evidence suggesting that they may be altered mitochondria.r8*T194 The hyperplastic lesion is limited to the outer zone of the medulla and inner cortex,
predominantly
the former.
frequently collecting
causing apparent ducts proximally.
ascending
limb
It involves
of the loop of Henle,
distal convolutions has been described
both
clear
and intercalated
luminal obstruction and consequent This dilatation occasionally extends but otherwise
cells,
dilatation of as high as the
the loops of Henle
and the
convoluted tubule, which are both normal .* The proximal as abnormal in potassium-depleted humans (see below),
is the site in rats, of an inconstant change beginning in its middle third and resembling the hyperplastic lesion of the collecting ducts, with cellular swelling and ultimate cell rupture followed by prolific regenerative hyperplasia. The cellular swelling in the collecting ducts and proximal convolutions is presumably lesion described in other studies,51.g3~‘64~230~24z~253 the “vacuolar” or “hydropic” cells of the *If it is true, as has been suggested by Oli~er’~~~ and Rhodin, z*7 that the intercalated collecting ducts are an extension of normal distal tubular epithelium, it is interesting that the distal convoluted tubule does not participate in the hyperplasia which so intensely affects intercalated cells in the outer medulla.
g;‘$$ \’
THE ,ONSEQUENCES
OF POTASSIUM
DEPLETION
225
and it is noteworthy that the collecting tubules were thought to be the site of a hyperplastic collecting duct lesion in two of the earliest reports on experimental potassium depletion.683164 Although in the microdissection studies demonstrating the collecting duct lesions the rats were alkalotic to varying degrees,rgl identical lesions are seen when rats are given acidifying ion-exchange resins causing potassium depletion with acidosis. 13’ The lesions are also independent of the sodium load.nO In contrast, the severity of the proximal lesion appears to depend on some undefined factors other than the potassium depletion per se, since it is far more striking and consistent in rats made acutely potassium deficient and alkalotic by peritoneal dialysis with sodium bicarbonate 140than in more slowly depleted rats. This may be but one of many situations in which such factors as rate of depletion, intake of other dietary constituents,lg6 and other aspects of wholebody or renal metabolism may condition the precise nature and severity of the renal lesions. The difficulty of defining renal damage as the consequence of a single electrolyte disorder is well illustrated by a recent study14* demonstrating that the proximal tubular lesion associated with phosphate loading is clearly accentuated by potassium deficiency (this proximal lesion is different than that of potassium depletion itself). Although agreeing in principle, this study did not confirm the recent suggestion of Selye and Bajuszz3’ that phosphate loading aggravates the lesions of potassium depletion. Rena1 calcification is not usually present in potassium depletion, but has been noted occasionally (usually calcium casts)g3~158J42and is prominent in the lesion of phosphate loading. r4* Interstitial changes are rarely mentioned, but several recent studies have shown alterations of intertubular ground substance and/or basement membranes in the medulla,51~‘g’~1g4 as well as apparently swollen interstitial cells, perhaps macrophages, which are periodic acid-Schiff positive.51Jg4 Inflammatory cell infiltrations are not characteristic of uncomplicated potassium depletion; neither are visible changes in glomeruli or blood vessels. A variety of enzymatic changes have been reported in the kidneys of potassium-depleted rats. Methods have varied and have involved both wholetissue ana1yses148,242 and histochemistry.5’*1g4J42 In general, however, there is a paucity of interpretable data on this obviously important problem, in that comparatively few enzymes have been studied by more than one group or by more than one technique. Alkaline phosphatase has been found 1ow182~242 and unchanged.51,1g4 Acid phosphatase has been apparently increased in the collecting tubu1es,51,1g4but was unchanged in another study .242Glutaminase activity (units per gram of kidney nitrogen) was increased in potassium-depleted rats as compared to pair-fed controls,148 as it was in the kidneys of potassium-depleted dogs treated with DOCA (but not when dogs were equally depleted of potassium without DOCA).14g It has been reported that nonspecific esterase increased in the proximal tubu1esrg4 but, using somewhat different histochemical methods, other investigators have found it unchanged .51*242 Succinodehydrogenase and the S-nucleotidases have been normal in two studies .51.1g4Other enzymatic findings have included increased activity of carbonic anhydrase (units per gram of nitrogen) ,148 unchanged arginase and amino acid oxidase,148 and variable alterations of lactic dehydrogenase depending on location in the nephron.18* Carbonic
226
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March, 1960
anhydrase in the dog kidney appeared to be depressed when potassium depletion was associated with DOCA treatment and was slightly elevated with potassium depletion on a high bicarbonate intake (without DOCA) but not when chloride replaced the bicarbonate.14g Increases in TPN-diaphorase and opposite changes in DPN-diaphorase have been interpreted as suggesting disturbed respiration and oxidative phosphorylation .lg4The possible significance of the increased glutaminase will be discussed later in relation to urinary acidification. In general, however, both the meaning and the validity of these various reported changes remain uncertain. Since protein depletion may cause depression of renal enzymes,‘48 protein depletion prior to potassium depletion may confuse results, although in this instance2Q the use of pair-fed controls largely negates this objection. Similarly, without more knowledge than presently available regarding the role of many nutritional factors other than potassium, the lack of pair-fed controls51 or an insufficiently detailed description of the control regimenig4 hampers interpretability. Since it is reasonable to suppose that some of the physiologic effects of potassium depletion are mediated through changes in intermediary metabolism, it is interesting that the concentration of pyruvate kinase, which requires potassium as an activator, has been found increased in kidney homogenates of potassium-deficient rats. 62 The increase was limited to the medulla and, when related to DNA-phosphorus, appeared to be a true hypertrophy per cell which more than compensated for the modestly depressed enzyme activity resulting from decreased renal potassium concentration. Although the rat and mouse are the only experimental animals in which the renal structural pathology of potassium depletion has been described, twice in potassium-depleted dogs it has been looked for with entirely negative results.205*240 This is of considerable interest and deserves further investigation.* Renal Structural Changes in Potassium-Depleted Humans.Knowledge regarding renal pathology in potassium-depleted humans comes entirely from three clinical situations, all of which represent potassium depletion, but in association with other metabolic abnormalities: (1) large losses of gastrointestinal fluid, (2) primary aldosteronism, and (3) potassium depletion due to renal potassium wasting of uncertain causation. The latter group35~71~‘67~172~2z7~267 (see Brooks and coauthors, Case No. 320) does not provide much helpful information about the effects of potassium depletion on the kidneys since, although many are probably examples of primary aldosteronism, they may also be one or another type of primary renal disease. Also, the several forms of “renal tubular not acidosis,” while commonly causing potassium deficiency, are obviously generally suitable material for studying the renal consequences of potassium depletion except when abnormalities can be shown to develop with the potassium depletion and to subside following potassium repletion. Perkins, Petersen, and Rileyigg appear to have been the first to ascribe anatomic changes in human kidneys to potassium deficiency. A patient died with almost certain potassium depletion as a result of a long-standing spruelike *Recent unpublished studies are reported to demonstrate renal tubular lesions in potassium-depleted dogs.176*
Volume Number
11 3
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
227
syndrome. The prominent histologic change was a vacuolization of the tubular epithelium which was thought to be mainly but not entirely in the proximal tubule. The vacuoles did not take fat stains, and the authors likened the lesion to that which had been described in potassium-depleted rats. A similar vacuolar or hydropic lesion of the tubular epithelium has now been reported in 16 other potassium-depleted patients, 4 with predominantly gastrointestinal causes of aldosteronism,6,30,37,43,45,55,70,86.'59,238 the potassium deficit, 34,156,213 11 with primary and 1 with gastrointestinal losses but also with chronic glomerulonephritis.35 In 8 of these30~37~55~156~15g~2’3 the lesions were thought to be mainly proximal, the validity of which was established in 4 instances by microdissection of nephrons.37J5 It is of interest, however, that there are 1.5 reports in which this “characteristic” hydropic lesion was apparently absent, 3 with gastrointestinal losses,203J13 9 with primary aldosteronism,6~20-2z~36~52J30~176 and 3 where renal potassium wasting was of uncertain cause. 20~172~267 This suggests that vacuolization is by no means a constant finding, although the significance of its absence in many of these studies is difficult to evaluate because of varying degrees of potassium repletion prior to obtaining kidney tissue. The vacuoles are apparently not Probably they represent glycogen34,45 and only rarely stain for fat. 3ov34,45,156,19g alterations comparable to those which develop in the collecting ducts and proximal tubules in rats,lgl although the evidence currently available suggests that in humans the proximal component is more prominent. Conceivably this may be conditioned by factors other than potassium depletion alone, as already discussed in relation to the rat pathology and perhaps supported by the apparent inconstancy of the lesion in human material. One interesting but wholly speculative possibility is that the vacuolization in proximal tubules is caused or aggravated by partial obstruction of nephrons due to collecting duct lesions such as are found in rats.lgl This suggestion stems from a note by Kulka, Pearson, and RobbinsrGo indicating the production of very similar-appearing proximal vacuolar lesions by ureteral obstruction in rabbits. Whether or not potassium depletion in humans causes collecting duct lesions comparable to those in the rat remains an important unanswered question which can only be settled by microdissection studies involving the entire length of nephrons. In the cases reported by Darmady and Stranack,55 the collecting duct was specifically stated to be normal in 1 instance3? and was not mentioned in the other 3; however, although nephrons were individually dissected, it was almost certainly impossible to study the medullary portion of the collecting system since the material was obtained by renal biopsy. Other structural changes in human kidneys appear to be due primarily associated to such conditions as hypertension aldostein primary ronism,6,20,22,30.37,45,52.70.86,176 h ypertension of uncertain cause,20v267and chronic pyelonephritis. 30,36,15g,176,183,203~213.215 It is noteworthy that a total of 14 potassiumdepleted patients have had complicating pyelonephritis as judged by history, urine cultures, or renal histology, 5,30.36,67.159,176,183.203.213.215.227although in at least 3 of these5~30~227 the pyelonephritis may well have preceded potassium depletion. Relman and SchwartzzL5 have suggested that this complication may be more common in the potassium depletion of primary aldosteronism than that of gastro-
228
WELT,
HOILANDEK,
J. Chron. Dis.
AND IILYTHE
March,
1960
intestinal disorders; however, this is not supported by the current review since 5 of the 14 instances of apparent pyelonephritis were in patients with gastrointestinal
causes
an incidence
of potassium
in this group*
a~dogteronigm.5.30,36~~59.176,1~3,215
been very
rare except
depletion,67J03~213 which
where otherwise
only
available
nephropathy after
information
in humans.
secondary
to
2 to 3 weeks recovery
as little
also
repaired
except
week of rapid
restoration
with
complete
of normal
potassium
be accomplished potassium
potassium
repair
depletion
several
with
renal architecture
collecting
In rats
may occur there
may
of glomeruli.164~253
rubidium
rather
than
in the inner medulla
repletion-in
months
scars in one).
hyalinization
tubules
provided depletion
repletion,164~175,253 although
and occasional
The hyperplastic
have
of potassium
in 2 patients
showed
lesion of collecting
following
as 2 days.n6
with primary changes have
and Schwartz2r3
reversibility
for some “pyelonephritic”
of tubules
can
rapidly
(except
following
sium.t2i5 The granular extremely
biopsies losses
complete
still be some dilatation Prompt
Serial
repletion
and mice, essentially within
regarding
gastrointestinal
potassium
at least as great
explainable.
Reversibility of Structural Changes.-Relman the
represent
as do the 8 cases which were associated A s in rats, glomerular and vascular
potas-
disappears
1 to 2 weeks175*182Jg4 or even in duct lesion,
although
ultimately
for occasional
fibrous scars, did not subside significantly within 1 repletion. I36 Most, but not all, of the enzymes studied
potassium
histochemically
by
days following
Pearse
potassium
structural
abnormalities
reversible.
In conflict
McCance,
and
enlarged
with
another,
comparable
atrophic,
Thus,
the consensus
develop
with
this conclusion,
demonstrating
after
complete hyalinized
study,i3’j
returned
MacPhersonrg4
which with
Parkerg
as long as 7 months
and repletion.
potassium
however,
very
potassium
normal
severe
within
depletion
is the study pathologic
repletion.
glomeruli
the results
to
has been that
and markedly
are
largely
of Fourman,
renal
The kidneys
were qualitatively
7
the renal
condition
were grossly
dilated
tubules.
In
similar
to those
of
Fourman, McCance, and Parker, but far less marked. Although differences in methodology may explain the quantitatively dissimilar findings, it is also possible that
the greater
renal
This
explanation
would,
tion
by Woods
accomplished,
and such
damage
was the
at least,
co-workers266 rats
have
result
be reasonable that,
increased
even
of superimposed long after
susceptibility
Renal Physiology in Potassium Depletion.Urinary concentrating power: There are many which
have
been
reported
in potassium
pyelonephritis.
in view of the recent
depletion,
potassium
to renal alterations the most
demonstrarepletion
is
infection. in renal
profound
function and con-
sistent of which is an impairment of the urinary concentrating mechanism. The earliest indication that this might be so derives from the studies of Loeb and associatess51z05 and from those of Mulinos, Spingern, and Lojkinrs4 demonstrating polydipsia and polyuria in dogs treated with DOCA. The maximum achievable urinary specific gravity was impaired’s4*205 and although the degree of polydipsia -____ *The very interesting reports of gastrointestinal disorders without documented potassium depletion but with pathologic renal condition resembling that seen in potassium depletion have not been included in this review since they can only provide a highly inferential form of evidence. They have been extenSiVely reviewed by Relman and Schwartz 213,215and by Coon and Johnson.44 tRubidium will also prevent renal structural changes in potassium-depleted rats.‘*
E%E11’
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
229
and polyuria was not significantly diminished when additional potassium was supplied,85 urinary concentrating power was not tested in this circumstance. Furthermore, although the potassium supplement prevented paralysis, the data suggest that it may not have completely prevented potassium depletion. Subsequently, Smith and Lasater *41 demonstrated a markedly increased water turnover in dogs on low potassium intakes ti’thout DOCA, but no data were presented regarding urinary concentrating capacity. Brokaw found similar polydipsia and polyuria in rats on potassium-deficient intakes, but concIuded that this was not due to impaired urinary concentrating power.18 However, it has now been clearly established both in the rat13gand dogm that potassium depletion does impair the renal concentrating mechanism. In rats the magnitude of this impairment appears related to the degree of potassium depletion,i39 and the defect occurs whether the potassium-depleted rats have extracellular alkalosis’3g or acidosis.138 It has recently been demonstrated that urinary concentrating power may be impaired if the excretion of urea is inadequate,8’si62 but this will not explain the results in potassium depletion, since some of the rats were pair fed with controls, since the rate of total solute excretion was never significantly lower in potassium-depleted than control animals, and since (in the one group in which it was examined) the rate of excretion of urea by potassiumdepleted rats was not depressed. 13g In dogs, maximum urinary osmolality is significantly depressed whether or not the potassium depletion is associated with administration of DOCA. ii2 It is not clear that the potassium-depleted dogs consumed as much food as controls, and the rate of solute excretion during testing was considerably lower for the DOCA-treated potassium-deficient dogs than for controls; hence, the possibility of inadequate excretion of urea mentioned above must be considered. However, this study”* also included measurement of the maximum negative free-water clearance (Tmc nzo) during mannitol diuresis, and, as this parameter was also significantly diminished, the explanation involving urea is unlikely. 16*Thus, the conclusion that potassium depletion impairs urinary concentrating power in experimental animals seems well established and is in agreement with other reported studies of this problemr75s2r8except for Brokaw’s,18 the results of which may have been influenced by methodologic problems as discussed elsewhere.13g In humans, a similar defect in the urinary concentrating mechanism has been the most prominent and consistent abnormality of renal function noted in association with potassium depletion. Thus, there are 33 instances of definite potassium deficiency due either to gastrointestinal losses or to primary aldosteronism in which maximum urinary concentration was specifically tested ,5~6,20~22~30~37~43~45~52~53~69~'~~86~124~~30~~35~143~159,~71,176,2~3,213,~34,238 and in all but 2 cases53r86concentrating power was clearly impaired. In an additional 7 cases with potassium depletion of uncertain causation, the maximum achievable urinary concentration was also subnormal.20~71J67*172~227~246,*6r In the vast majority of all of these cases the maximum urinary specific gravity was less than 1.015. This case material also demonstrates that, as in experimental animals, the concentrating defect is not related to extracellular acid-base status or to high levels of mineralocorticoid.
230
WELT,
Currently
available
of how often
the
data
renal
potassium repletion and this is also true
HOLLANDER,
do not provide
concentrating
In addition,
there
power, but the longest for most it is less than
only
3 case
reports
had chronic initial
showing
following
pyelonephritis
only 255 months the
are 13 instances
power
is completely
occurring from cure of primary
concentrating months and are
an answer to the important
defect
question
reparable.
In rats,
restores normal urinary concentrating ability rapidly136**75 (or nearly so) for the dog. I” Among human cases, there are
8 examples of complete reparability potassium repletion and/or surgical
centrating
J. Chron. Dis. March, 1960
AND BLYTHE
essentially
in addition
been
period
no improvement however,
to potassium
removal
restoration
of urinary
in this group
is only
~21,22,43,45,52.69.130,172.203,213,238
repletion; of an adrenal
impairment
is uncertain.5 ft has previously
partial
follow-up 6 months
potassium
after surgical
concentrating
demonstrating
1% to 15 months following aldosteronism.6~70~‘~4~~35~143~~34
was slight
in urinary 1 of
the
depletion,r76 adenoma,37
12
There
con-
patients
1 was tested
and in the third
and the duration
of follow-up
suggested lgl that the urinary concentrating defect of the lesions which have been demonstrated in
may in some way be the result the collecting
tubules.
This
is a reasonable
hypothesis
since it is now recognized
that the hyperosmotic concentration of urine is established in the collecting ducts.n6e264 However, the loops of Henle and the distal convoluted tubules are also importantly retically, several
involved
potassium ways:
in the renal concentrating
depletion
could
(1) by interfering
impair
process12J16,264 so that,
urinary
with the hyperosmotic
concentrating reabsorption
theo-
power
of sodium
in and
the counter current multiplier system in the loops of Henle, since together they apparently create the high osmotic concentrations which are established in the interstitial final
fluid of the medulla
abstraction
reabsorption established
of water
water
is largely
between
second
centrating
reabsorption
through
possibility in
to be responsible
ducts;
(2)
by
(isosmotic)
urine distal
the wall of the collecting
has been
reasonably
potassium-depleted
urine in the initial
the early
are thought
collecting
the first and third of these possibilities
defect
hypotonic
the
for the
impairing
water
in the distal convoluted tubule where isotonicity is normally by water transfer out of an initially hypotonic fluid; and (3)
impairing The
and which
from
further tubulen7
portion
along
excluded rats
since
of the distal
in the distal
also suggests
that
The choice
and remains as the cause such
convoluted
rats
unresolved. of the con-
have
tubule
convolution.*
The
hyperosmotic
sodium
in the terminal segment of the ascending
is not impaired
ducts.
reby
normally
and normal
hypotonicity
in
reabsorption
limb of the loop of Henle,
but it does not indicate more than that regarding the functional state of the countercurrent multiplier system. Manitius and colleagues’73 have compared the tonicity of deep medullary tissues in normal and potassium-depleted rats but obtained data which do not clearly exclude either the first or the third of the above theoretic explanations for the urinary concentrating impairment. Further investigation is certainly indicated and, as already discussed, the collecting tubules in cases of human potassium depletion need careful study. *The potassium
recent
studies
depletion
may
of
Giebisch
inhibit
and
water
Lo~ano”~
reabsorption
present in the
evidence distal
which
tubule.
suggests
that,
in
the
dog.
“N:!%-:r :
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
231
Urinary acidification and bicarbonate excretion: Since very large intakes of sodium bicarbonate produce little or no alkalosis in the absence of potassium depletion,49~“4 the propensity to develop metabolic alkalosis in association with potassium depletion is itself evidence of impaired bicarbonate excretion (or impaired chloride reabsorption). This aberration of tubular function has also been demonstrated in a variety of acute experiments in dogs,‘r3 rats,4g and humans.*~~~~~~~~~~220~221 The corrolary of this is, of course, that in the presence of any tendency toward extracellular alkalosis the kidneys of a potassium-depleted subject excrete urine which is inappropriately acid. Frequently the urinary pH is less than 7.0, which has led to the term “paradoxical aciduria,” but this term might more reasonably be used to imply that acid excretion and bicarbonate reabsorption exceed what is appropriate in relation to the extracellular acid-base status. Many examples of this tubular defect could be cited. Thus, the urinary pH was less than 7.0 despite significant extracellular alkalosis in several experimental studies involving potassium-depleted dogs,n3~180 rats,48,4gJ48and humans.14,82,243,265 In the reported cases of primary aldosteronism the urinary pH has varied between 6.0 and 7.5 and, although probably more alkaline than in other forms of potassium depletion, it is not consistently greater than 7.0, as has been suggested.6gs130It is now generally accepted that, as indicated earlier in the section on pathogenesis, the secretion of potassium and hydrogen ions by the renal tubule is in some manner competitive, and it has therefore been proposedi that the relatively increased excretion of acid by potassium-depleted kidneys is due either to a deficiency of potassium in the renal tubular cells or to what is usually considered to be the corrolary of this, increased availability of hydrogen ions in these cells. This concept is supported by the finding that when slices of rabbit kidney cortex were depleted of potassium and incubated with NaHC03 their final bicarbonate concentration was less than that of slices with normal potassium content3 Thus, reabsorption of sodium by the ion exchange mechanism results in a proportionately larger secretion of hydrogen ions and lesser secretion of potassium. The relatively more alkaline urine in primary aldosteronism is also expected from this hypothesis, since in that condition urinary potassium excretion remains high (more than 25 mEq. per 24 hours) despite serum potassium concentrations of less than 3.0 mEq. per liter and the presumably low levels of intracellular p~~~~~~~~,~~29~37~43~46~~3,70,Y9~99~124~~35,143~171,176,238 This is in distinct con_ trast to the generally low levels of urinary potassium (less than 20 mEq. per 24 hours) seen in patients with gastrointestinal losses as the cause of potassium depletion,67,213.234,261 in human subjects experimentally depleted of potasef_ animals. 48,49,93,149,192,242 The sium,14~15~40~82~g5~210~265 and in potassium-depleted feet of mineraloco’rticoid in augmenting potassium excretion despite potassium depletion has also been noted in dogs.149 Potassium depletion appears to cause an increased excretion of ammonium ion (considered in relation to the almost neutral urinary pH which is usually present). This has been noted in primary aldosteronism,7°~176*z44and an acute increment in ammonium excretion has been observed when DOCA was added to a *It has also been shown zz1that an infusion of potassium into normal dogs inhibits the elevated bicarbonate reabsorption normally associated with an elevation of pco2.
232
WELT,
potassium-deficient se, however,
HOLLANDEK,
AND
J. Chron. Dis. March, 1960
BLYTHE
regimen. 145That it is not a function of mineralocorticoid per by several studies of experimental human potassium
is illustrated
and in 2 patients whose potassium depletion was the result depletion 4ov226*243~265 of gastrointestinal losses. 234 The ca:rse of the increased ammonium excretion is uncertain, but has been ascribed to the increased glutaminase previously discussed.r4* Similar rises in renal glutaminase
have been noted in rats chronically
treated
in which
with
elevated due
Diamox,20g
another
in the presence
to ammonium
of relatively
chloride
in all of these situations the suggestion activity
situation
alkaline
administration.
is the presumed
that intracellular
seems a reasonable
acidosis
urine,
208 Since
increase
ammonium
excretion
and in metabolic the common
in intracellular
is the stimulus
is
acidosis
denominator
acidity
for increased
or pCOn,
glutaminase
one.2og
In addition impairs urinary
to these alterations, it has been claimed that potassium depletion acidification, i. e., that despite the inappropriate acid excretion described, there is actually a limited ability to acidify the urine. There is
already
essentially data
no support
indicate
very
for this in animal
low urinary
with severe acidosis
pH levels
(presumably
experiments in acutely
respiratory,
since
the only
relevant
potassium-depleted
secondary
to weakness
dogs87
of respira-
tory muscles). The concept derives primarily from two studies of experimental potassium depletion in human subjects. Clarke and associates40 produced potassium
depletion
and
then acidosis
that the potassium-depleted and a higher slight:
subject
final urinary
pH
with
ammonium
responded
than did controls.
the rates of fall of urinary
pH appear
chloride.
with a slower However,
almost
They
observed
fall in urinary the differences
identical,
pH were
but the potassium-
depleted subject started at a higher pH (6.4 versus 5.5) ; the minimal urinary pH of the potassium-depleted subject (5.2) was only slightly higher than that of controls
(4.5 to 5). Nonetheless,
by finding ment)
that urinary
potassium
the validity
pH increased
depletion
of these differences
was strengthened
from 4.7 to 5.3 when (in a different
was superimposed
on already
existing
experi-
ammonium
chloride acidosis. On the basis of these observations, plus experiments measuring titratable acidity during an infusion of neutral sodium phosphate, the authors concluded
that potassium
not the maximum gave
ammonium
depletion
rate of hydrogen chloride
ion excretion.
to experimentally
noted a less acid urine and a smaller larger increment
limits maximum
of ammonium
increment
excretion
hydrogen Rubini
ion gradient
but
and coauthors226 also
potassium-depleted in titratable
than with controls.
subjects
acidity,
and
but a much
Qualitatively
similar
finding-s have been reported in 3 patients with primary aldosteronism,5JlJ2*70 but in 3 others urinary acidification was little, if at all, impaired.37J14 Hence, potassium depletion may impose some limitation on maximum hydrogen ion gradient in the urine, but this is not clearly established and there is no evidence of impaired capacity There is some
for total acid excretion. evidence that potassium
depletion
depresses
excretion
of
organic acids. This has been shown in potassium-depleted alkalotic rats83 and in 2 human subjects with potassium depletion and acidosis.*g8 There is some further support for these findings in two other studies of experimental potassium -____ *In rats the largest fraction
of the urinary organic acids is alpha-ketoglutarate;
in man it is citrate.83
THE CONSEQLENC’ES
OF POTASSIUM
DEPLETION
233
depletion in humans.4”,s’” In rats, repletion with potassium bicarbonate is followed by increased excretion of organic acids without change in their plasma level, but interestingly this does not occur when repletion is accomplished with potassium chloride.4’-4g,83 Organic acids were similarly unchanged during repletion of 2 patients with potassium chloride, 234but did increase in 2 others.ls3 The significance of these findings is not yet clear and more studies are needed. Cooke and associates4’,4g have suggested that the organic acids may facilitate chloride conservation by serving as essential anions, allowing the excretion of large quantities of cation without chloride and without rise in urine pH. Other renal functions: It has been suggested17? that potassium depletion may impair renal tubular reabsorption of phosphate, but in the case presented the evidence was not conclusive since there were alternative explanations. None of the very meager evidence from animal studies supports this concept48,4g*g3,21g except for one report which shows an apparent decrease in phosphate Tm. during acute lowering of the serum potassium concentration.‘34 There are three studies of experimental potassium depletion in humans (two alkalotic and one acidotic) during which urinary phosphate excretion rose,14*82,g5but there are no studies of phosphate Tm. in potassium-depleted humans, and the subject remains unresolved. The possibility of aminoaciduria as a result of potassium depletion has not been studied in animals and is only rarely mentioned in relation to potassiumdeficient patients. Denton and associates64 reported 2 instances of aminoaciduria which they related to potassium depletion, but the relationship was not established with certainty. Stanbury and Macaulay248 also reported aminoaciduria in association with potassium depletion, but again the data do not particularly suggest a cause and effect relationship. Urinary aminoacids have been normal in 2 cases of primary aldosteronism.21~22*70 Other findings in relation to renal tubular function in potassium depletion have included: normal glucose reabsorption in dogsn2J78 and presumably in humans since renal glycosuria has not been a feature of reported cases; normal capacity to conserve sodium maximally,6J34~*43 although Mahler and Stanbury”* have described a patient with chronic renal disease and a potassium-wasting tendency in whom intermittent impairment of sodium conservation was thought to be the result of intermittent potassium depletion; and apparently normal conservation of potassium itself, 48.49,67.93,149.157.192,213,234,242 which remains almost maximal even in the face of stimuli (such as acute bicarbonate loading) that normally cause increased potassium excretion.40~49~8* One interesting report suggests that, under some circumstances, urinary potassium excretion may reach a minimum and then increase somewhat with progressive potassium depletion. In 2 hypokalemic, alkalotic dogs on a low potassium, high bicarbonate intake (without DOCA), the average daily urinary potassium excretion rose progressively from 0.8 mEq. after 1 week to 4.5 mEq. after 4 weeks.*4g The data presented, however do not, indicate whether or not this could have been due to increased catabolism. Changes in the glomerular filtration rate (GFR) are not striking in potassium depletion and, since glomeruli are not visibly damaged, such reductions as do
234
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March, 1960
occur are probably best explained by the obstruction of nephrons discussed earlier. Measured as the clearance of inulin (Cm), mannitol, or endogenous creatinine, the GFR was either normal or only mildly depressed in all but 2 patients3’v1” of 16 with primary aldosteronism. 6.20,21,22,3’,43,45,69,70,86,124,130,143,171,176,238 When potassium deficiency is due to gastrointestinal causes there may be a somewhat greater tendency for the GFR to be low, ‘15but even SO it is not severely decreased and in 4 of 8 patients it was only mildly so or normal.*67,213,234,26’ Similarly, the serum level of nonprotein nitrogen, (NPN), urea nitrogen (BUN), or creatinine has been elevated in only 3 of 17 patients with primary aldosteronism and in 5 of 10 patients with gastrointestinal losses.1,67J35,213 In 4 experimentally potassium-depleted humans with negative potassium balances of 113 to ,543 mEq., there were no significant changes in the endogenous creatinine cIearance.96*265 In rats, potassium depletion appeared to cause a slight decrease in the endogenous creatinine clearance,l*‘j but the possibility of simultaneous protein depletion as the explanation was not excluded. The BUN may remain normal in potassiumdepleted rats13*or may increase by more than 100 per cent, as may the NPN.97~242 In dogs, the creatinine clearance may remain constant or may decrease slightly with potassium depletion, 112,180 but again it is not clear that the decreases were not the result of diminished protein intake. In contrast, dogs rapidly depleted of potassium by extracorporeal dialysis, with acidosis (presumably respiratory) and apparently unchanged body water, had 50 per cent reductions in GFR (Cm) without change in effective renal plasma flow (clearance of para-aminohippurateCp~n).*~ This interesting observation cannot be explained by the respiratory acidosis66a132 and did not occur in control studies using the same dialysis procedure but without potassium depletion, which points up a need for further investigation of this and other parameters of renal function in rapidly potassium-depleted animals. During a period of a few weeks to 15 months following surgical cure of primary aldosteronism (and potassium repletion), the GFR occasionally has increased to norma1124J43,171; but more often it has fallen (sometimes only transiently), presumably because of the drop in blood pressure and renal vascular disease.37r69*70J76 The only similar studies on patients with gastrointestina1 causes of potassium depletion are those of Relman and Schwartz213J34which showed increases to normal in 2 cases, increase almost to normal in 1, and very little change in 1 (but there was doubt as to the adequacy of potassium repletion). The clearance of para-aminohippurate is frequently somewhat depressed but this is probably a reflection in potassium-depleted patients, 37,6g,159,171,213,234 of another renal tubular defect, the extraction and secretion of PAH,171J34J51 and may not indicate any reduction in renal plasma flow except where renal vascular disease is also present. A similar explanation presumably accounts for the frequently encountered moderate depression of phenol red (P. S. P.) excretion 34,53,135,213,234 Although it has been suggested that potassium deficiency may cause acute oliguria,120 this has not been a recognized consequence of potassium depletion, *Two of the% patients6’*% had normal or almost normal glomerular sium repletion. but data during depletion are not available.
flltration rates just after potas-
F”‘:E7
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
235
and the evidence in this and one other instance 67strongly suggests that the oliguria was due to causes other than the associated potassium deficiency. Potassium-depleted patients usually have either mild proteinuria or none. The urinary sediment is most commonly unremarkable, but occasionally contains a few red cells, white cells, and/or casts. Relation of Alkalosis to Renal Damage.-One of the important unsolved questions closely related to the renal effects of potassium depletion is the effect of alkalosis on the kidney. As indicated in the section on pathogenesis, extracellular alkalosis is commonly and perhaps invariably accompanied by a potassium deficit; it is therefore entirely possible that the renal impairment which has been partially attributed to alkalosis25~26is in fact the result of potassium depletion (plus undoubted dehydration and sodium depletion in many instances). In the rat there are no lesions associated with potassium depletion and alkalosis that are not also seen when the potassium deficiency is produced in association with acidosis.137 Similarly, there is no evidence that renal structural damage or renal functional impairment is any more striking or of any different type in patients with primary aldosteronism, in all but a few of whom5,22,30,37,62.143 alkalosis has been a prominent feature, than it is in patients with potassium depletion secondary to gastrointestinal causes, in whom alkalosis has usually been minimal or absent. Hence, it is tentatively concluded that alkalosis per se is not damaging to the kidneys, but the matter cannot be settled until and unless severe alkalosis can be produced experimentally without potassium depletion (or with very minimal potassium depletion), which, as shown by Cooke and co-workers,4g is at least difficult. POLYDIPSI.4
The polydipsia commonly associated with potassium depletion may be secondary to the impaired renal concentrating process, but this is not established and there are reasons for believing otherwise. Furthermore, there is uncertainty as to whether the polydipsia associated with primary aldosteronism and with DOCA administration in animals is due to potassium depletion alone or to potassium depletion plus another effect of mineralocorticoid. The latter question is unsettled because, although potassium depletion alone clearly can cause polydipsia,18~g5~1ag~241~242 the polydipsia of dogs treated with DOCA was not ameliorated by potassium chloride supplementation,85 and polydipsia seems to be a considerably more prominent symptom in primary aldosteronism (mentioned specifically in 16 of 25 case reports) than it is in patients with potassium depletion due to gastrointestinal causes (mentioned in only 1 of 9 case reports). Also of interest is 1 patient70 in whom thirst and polyuria sudsided rapidly following surgica1 removal of an adrenal adenoma, although the balance data suggest that 80 per cent or more of the potassium repletion had been accomplished before the operation. On the other hand, it has been reported that administration of DOCA does not cause polydipsia in rats, provided the sodium intake is very low,205one possible explanation for which would be that, as is now known,212*236 little or no potassium depletion develops on such a regimen. It has also been reported that, in contrast to the observations of Ragan and
36
WELT,
HOLLANDER,
AND
J. Chron. Dis. IMarch, 1960
BLYTHE
DOCA-treated potassium-depleted associates205 already mentioned, less polyuric when they are repleted with potassium while DOCA
is continuedr*O;
however,
it is not known
the polydipsia)
subsided
completely,
whether
which
the polyuria
is the
crucial
dogs become
(and presumably
information
needed
to answer
this
question. There that
the
is considerable polydipsia
corticoid the
or not,
result
may
of renal
or 2 after centrating
circumstantial
of potassium
evidence
dificiency,
be a primary
concentrating
effect
depletion, begin
it may
hypothesis
by mineralonot
merely
within
a day
animals are placed on a low-potassium diet, before the renal condefect is marked and possibly before it is even demonstrable*1~~139~24*~*42;
mechanisms the result
than
in 2 of the controls,13g
of a tendency
osmolality;
toward
(3) dogs treated
may
their
(1)
the
aggravated
of potassium
impairment:
(2) the average serum solute concentration mOsm. lower in 3 potassium-depleted rats
ism
supporting
whether
have
suggesting that the polydipsia is not and consequent elevation of serum
with DOCA205 and patients
spontaneous
demonstrated
dehydration
measured cryoscopically was 10 with impaired renal concentrating
urinary
specific
with primary
gravities
maxima,21*22~143 or as noted
which
are
by Stanbury
aldosteron-
clearly
they
below
have
urine
volumes which exceed what could be explained by the concentrating defect alone; (4) as has been observed in two experimentally potassium-depleted humanstY and in several patients with primary aldosteronism, 52,53the thirst may be relatively unrelieved rapidly if any, with
by drinking
after
surgical
improvement
primary
concentrated
urine
An attempt
While
it fails fails
imposed EFFECTS
very
in renal
concentrating
(maximum
urinary to prove
and before
power37~45~70~15g; and despite
specific
normal
gravity
primacy
may there
subside is much,
(6) one patient
ability
to produce
of 1.027).
of the polydipsia
by nephrec-
potassium-depleted rats, but spontaneous water ingestion was no greater than that of nephrectomized controls.263
to support
causes
(5) the polydipsia
aldosteronism
53 had polydipsia
has been made
to negate
transiently;
of primary
aldosteronism
tomizing polydipsic after nephrectomy also
except cure
such
the
hypothesis
a hypothesis,
for a diminished
thirst
of a primary since
there may
after
polydipsia,
this
result
well have
been
super-
nephrectomy.
ON THE HEART
The Heart Lesion.-Myocardial lesions have been noted in experimentally produced potassium deficiency in rats,~0~93~‘0*~‘58~‘70~*oO~*30~~55 mice,lc4 pigs,*55 and cats,6o but not in dogs60.240; they have been found in humans dying from conditions associated with potassium deficiency.*15~‘56~‘67~16g~‘gg~B3 The have
essential
been
found,
feature
of the lesions,
is necrosis
of cardiac
common muscle.
to all species Although
in which
they
it has been reported
*The possibility that the polydipsia is actually the cause of the renal concentrating defect’39 has been excluded.‘90 tThese are the only experimentally potassium-depleted humans in whom thirst has been a reported symptom. It is, therefore. interesting that they were more severely depleted than any others with negative potassium balances quite comparable t,o those seen in potassium-depleted patients (839 and 674 mEq.)
Volume 11 Nlml>er 3
THE CONSEQIXNCES
OF l’OTASSIITM
DEPLETION
237
that they occur,p;lu endocardial lesions have generally not been seen in experimental studies; however, the subendocardial areas are apparently the most extensively invo1ved.g3J02J70 The earliest changes consist of swelling and loss of striations of muscle fibers.170 The fibers gradually become necrotic and finally disappear, leaving the containing sarcolemma. Soon afterward or simultaneously, the nuclei begin to shrink and undergo karyolysis or karyorrhexis. Associated with these changes there is an immigration of leukocytes into the areas of necrosis. Early, the leukocytes appear to consist largely of polymorphonuclear neutrophils, but it has been noted that the cells appearing to be predominantly polymorphonuclear neutrophils are actually dark-staining tissue macrophage nuclei, very prominent capillary endothelial nuclei, and only an occasional polymorphonuclear neutrophil. “O Later the tissue macrophages clearly predominate. Whether or not destruction of the existing connective tissue framework with later proliferation of scar tissue occurs in the areas of necrosis is in dispute. The earlier reports indicate that destruction of the framework with subsequent proliferation of connective tissue does occur. French,lo2 however, using more elegant staining techniques, found that although there is collapse of the supporting stroma, no destruction occurs. But he did note some proliferation of vascular endothelium and fibroblasts, indicative of proliferation of connective tissue, even though there was little evidence of formation of new collagen fibers. More recently, McPherson,17o in reassessing the lesions, has proposed that all the changes are secondary to degeneration and death of muscle fibers, phagocytosis of necrotic material, and collapse and condensation of the supporting stroma. As evidence for lack of proliferation of connective tissue, he found no capillary ingrowth, lack of fibroblastic response, and virtual absence of polymorphonuclear neutrophils. He contends, reasonably, that since connective tissue has a very low potassium content, there is no apparent reason why it should be sensitive to potassium lack. It is his impression that if cardiac muscle were capable of complete regeneration, the normal architecture of the heart could be restored, a situation analogous to certain cases of hepatitis in which connective tissue is not damaged and restitution of the normal architecture ensues. Another interesting feature of the lesion is the accumulation of a substance which stains red with Schiff-periodic acid stain in damaged muscle fibers, tissue macrophages, and muscle cells bordering the necrotic foci.102J70 It is thought that the material in the tissue macrophages might represent excess ground substance that is being removed, since prior treatment with diastase does not abolish the staining properties, indicating that the substance is not glycogen. The material in the damaged and ambient muscle fibers is most likely glycogen, since it does not stain after treatment with diastase.l’O Why these myocardial lesions should result from potassium depletion remains unknown. A deficit of body potassium is apparently essential for the production of the lesions, and in rats there is evidence that heart potassium is decreased. Attempts to produce the lesions in dogs, however, have been unsuccessfu160.240 even though in several instances the potassium content of heart has been decreased.6o Reports attesting to a protective effect of pyridoxine256
238
WELT,
HOLLANDER,
AND
BLYTHE
J. Chron. Dis. March, 1960
and a deficiency of thiamine go have not been confirmed.60 Digitalis has been reported to have no effect on the incidence or appearance of the lesions.z** The lesions are more extensive in potassium-depleted rats which are violently exercised.gr It has been stated that the addition of sodium to the diet enhanced the severity of the lesions32 although this effect was attributed to an increased sodium content of the cells, it might simply be the consequence of a more intense deficit of potassium due to the sodium load. Perdue and Phillips’96 claim that a diet with a 20 per cent content of corn oil induces more striking lesions than a diet with only 5 per cent corn oil. They claim there was no difference in skeletal muscle potassium, but the data suggest that there might have been. It should be emphasized that the appearance of the lesions is not unique. Its similarity to the myocarditis associated with diphtheria has been recognized and it has been described as resembling focal myocytolysis,i70 a type of necrosis associated with coronary artery disease.22g Although the myocardial lesions have been reported in humans dying from diseases which are associated with potassium deficiency, for example, diabetic acidosis,*23 steatorrhea,i56J69 and adrenal cortical insufficiency treated with excessive amounts of DOCA,rr5 conclusive evidence for potassium deficiency in these cases is lacking. McAllen 16gstates that in case 1 of his 2 cases, “An electrolyte balance was carried out two weeks before death. This showed a retention of Na and a markedly negative balance for K, the latter being attributable to abnormal loss of potassium in stools.” However, no figures were published. Nevertheless, the clinical situations in all the reports are indicative of potassium deficiency, and the lesions described are in general similar to those reported in experimental potassium deficiency. In several cases, it seems quite likely that coronary artery disease was also present,16gr223 and it may be that in certain of the cases in which massive scarring is reported the changes are secondary to ischemia. Some of the scattered foci of necrosis might also represent the focal myocytolysis associated with coronary artery disease. The Electrocardiogram.-Alterations in the electrocardiogram are a frequent accompaniment of hypokalemia. This is not surprising, since changes in extracellular concentration of potassium have been shown to affect markedly the electrical activity and excitability of the myocardium. r9 Changes in practically every part of the electrocardiogram have been reported, and there is no consistent pattern of hypokalemia.6~1*6,166,216,?46 Th e most commonly observed changes, particularly in man, are depression of the S-T segment, decrease in amplitude and inversion of the T wave, and exaggeration of the U wave. Although prolongation of the Q-T interval has often been reported as an accompaniment of hypokalemia, there is evidence that it is normal in duration and that the apparent prolongation is a resultant of including the U wave in measurement of the Q-T interval.‘26J68~248 Other changes that have been described are increase in the amplitude of the P wave, prolongation of the P-R interval,25g and widening of the QRS coma change usually associated with hyperkalemia. plex, 250~26g Whether these abnormalities are secondary to a decreased extracellular concentration of potassium, a decreased intracellular concentration, or a change in the ratio between the two is not definitely known. These questions have
E%zr‘3’
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
239
remained unanswered largely because of the difficulty in measuring intramyocardial potassium in preparations suitable for recording electrocardiograms. Information which is appropriate, however, has been obtained about the correlation of the electrocardiogram with extracellular and intracellular concentrations of potassium. Schwartz, Levine, and Relma@ analyzed the relationship of the electrocardiographic changes to serum concentration of potassium as well as to total body deficit of potassium in humans in whom varying degrees of potassium depletion had resulted from diarrhea or from administration of DOCA, compound F, or acidifying salts. They found that the electrocardiogram revealed evidence of potassium depletion in only one-half their observations. It was often normal with low serum potassium concentrations and was occasionally abnormal with normal serum concentrations. They concluded that the electrocardiogram was not consistently related to either body deficit or serum concentration of potassium. Experiments have also been performed on dogs in which electrocardiographic changes were related to changes in serum concentration of potassium as well as to varying degrees of total body deficit of potassium. Weller and coauthors,25g utilizing hemodialysis, noted that potassium extraction occurred in two phases: a first phase during which there was a rapid decline in serum concentration of potassium and during which potassium was being removed from the extracellular and intracellular compartments, and a second phase in which the serum concentration of potassium remained constant and potassium was, therefore, presumably being removed from the intracellular compartment. Changes in the electrocardiogram observed throughout the experiments were analyzed. Alterations limited to the first phase consisted of increases in the amplitude of the P wave, prolongation of the P-R interval, and rounding of the T wave. Changes limited to the second phase, when potassium was presumably being removed from the intracellular compartment, were depression of the S-T segment and widening of the QRS complex. Shifts in the QRS axis and the acceleration of heart rate were observed throughout both phases. Similar changes in the electrocardiogram have been observed in experiments with isolated, perfused turtle and dog hearts when the perfusate was potassium free.28 Another line of investigation which has yielded pertinent data is exemplified by the studies of Grob, Johns, and Liljestrand. While studying the movement of potassium in and out of muscle of normal subjectsug and patients with familial periodic paralysis, li8 they recorded ECGs following manipulations which produced hypokalemia by effecting transfer of extracellular potassium into muscle cells. When the arterial concentration of potassium had been decreased below 3.3 mEq. per liter, they noticed in both groups a positive after-potential on the falling limb of the T wave (U wave) as well as slight prolongation of the P-R, QRS, and Q-T intervals and lowering of the T wave. Qualitatively the changes in the electrocardiogram found in these various experiments are quite similar, but the underlying common denominator is not evident. It should be re-emphasized that it is not reasonable to equate derived changes in intracellular potassium or changes in muscle potassium with what
240
WELT,
HOLLANDER,
AND BLYTHE
J. Chum. Dis. March, 1960
is happening in the heart and, until the electrocardiogram can be compared with samples of intramyocardial and extracellular potassium simultaneously obtained, the exact relationship among the three will probably remain unknown. The practical aspect of these considerations is that, at present, the electrocardiogram cannot be relied upon as an indicator of potassium deficiencyeither extracellular or intracellular-for the reasons previously mentioned and also because of other accompanying derangements in extracellular ionic composition which affect the electrocardiogram. Nevertheless, when electrocardiographic patterns consistent with hypokalemia are observed in patients, the presence of potassium deficiency should be verified or excluded by more reliable means. In addition, the electrocardiogram is useful in the therapy of potassium depletion to assist in avoiding the development of hyperkalemia. Arr/zytythmius.-Disturbance in heart rhythm is another of the consequences of the increased excitability of cardiac muscle that results from potassium depletion. The most common accompanying arrhythmias are auricular and ventricular extrasystoles which may or may not be coupled. Auricular tachycardia and auricular flutter have occasionally been observed also.’ It has been in the area of the interrelationship of potassium and digitalis, however, that potassium depletion as a cause for arrhythmias has received the most attention. For many years potassium salts have been used extensively to abolish arrhythmias resulting from exhibition of excessive digitalis and where there has been no evidence of potassium deficiency. Formerly, opinion was that the efficacy of potassium in restoring normal rhythm was due to a pharmacologic effect of reducing myocardial excitability. Since it has been found that toxic doses of digitalis compounds may reduce myocardial concentration of potassium,42f125 it has been suggested that the administration of potassium salts may result in restitution of myocardial potassium to normal. 165 Recently, attention has been called to paroxysmal auricular tachycardia with block’66 as being a particularly common resultant of imbalance between digitalis and potassium. Heart FuiZure.-Signs and symptoms suggestive of congestive heart failure have been observed in several studies of potassium depletion in rats 31,200,242; however, no objective measurements indicative of heart failure have been made. Because of the complexity of the clinical situations in which potassium depletion is usually found in man, it is difficult to ascribe the presence of heart failure to potassium depletion. There have been several reports’03~‘06 of cardiovascular abnormalities including congestive heart failure, occurring in the presence of hypokalemia, which disappeared following the administration of potassium. EFFECT
ON BLOOD PRESSUKE
Lowering of the blood pressure has apparently been produced by potassium by unilateral deprivation in normal ratslo and in rats made hypertensivelO nephrectomy plus the placing of a ligature on the remaining kidney. Recently, it has been found the aortic wall content of potassium is higher in rats made hypertensive by this method than in normal rats and that potassium deprivation leads to a decrease in the potassium content of aortic wall in hypertensive rats as well as in normal rats.101 This has led to speculation that arterial tone is
11 3
Vrhme Number
THE
regulated
(‘ONSECJIEN(‘ES
by concentration
OF
I’OTASSII’M
of potassium
in the arterial
the efficacy of potassium deprivation in lowering PererarY* observed that potassium restriction small
but
EFFEC’TS
statistically
ON
significant
decreases
THE GASTROINTESTINAL
Almost
all
investigations
intestine
which,
of congestion
of the
mucosa
and mononuclear ocytes.
In the
of potassium
edema
into its constituent these studies and
depletion
tassium
but not alkalotic.
was segmental,
patches
of small
depletion
annular
and
in the
and dissociation
on several and
of gastric
They
changes
functions
juice
were present
have been amplified
by Perdue
of acetyl-beta-methylcholine rats
but
not in normal
increased
the effect
of po-
deficient
in po-
made
in pH, decrease in sodium
in titratable concentration
rats
is due to a lack of stimuli EFFECTS
and concluded
rather
motility
that
than an inability
results These
injections
in potassium-depleted
the limited
peristaltic
of the smooth
activity
muscle to respond.
ON METABOLISM
Carbohydrate Metabolism.-That are
and Phillips*g7 who found that intestinal
in
of the gastrointestinal
in rats
and an increase
phag-
intestine,
of the pancreas
Cooke33 studied
found an increase
concentration,
large
of gastric juice. In addition, it has been found that potassium depletion in a decrease in the motility247~258 and propulsive abilityi of the intestine. findings
have
thickening
filled with mononuclear
intestine
Edema
Carone
on composition
potassium
species
examination, was found to consist villi engorged with lymphocytes submucosa,
abnormality.
investigated.
tassium
and
in several
lobules were also noted. Why these absent in others is not apparent.
has also been
acidity
and areas
The effect of potassium tract
depletion
intestinal tract, although distention In two studies on rats, quite similar
feature
and Peyer’s
was the outstanding
men produced
pressure.
on microscopic
phagocytes, intervening
blood
explaining
TRACT
were found.15RJ30 A prominent
of the small
wall, thereby
blood pressure. in hypertensive
in resting
revealed no pathologic alterations in the of the bowel has been frequently observed. changes
241
DEPI,ETION
interrelated
is evident
from
potassium in vitro
and
experiments:
carbohydrate deposition
metabolism of glycogen
in the liver is accompanied by deposition of potassium84; potassium is essential in the phosphorylation of the adenylic system16f17s153; anaerobic glycolysis is inhibited and aerobic of incubating requires
glycolysis rabbit
potassium
is stimulated
by the addition
of potassium
to medium
brain
s1ices4; and optimal glycogenesis in rat liver slices concentrations higher than that of extracellular fluid in order
to maintain a normal intracellular concentration,lz2 whereas increasing potassium concentration in the medium of incubating rat diaphragm inhibits glycogenesis.2g Potassium
depletion
in rat
liver
slices
leads
to decreased
glucose
uptake,
increased glucose output, and increased glucose formation from pyruvate, as well as decreased glycogenesis .iz2 These phenomena are similar to those found in diabetic rat liver slices and have led to the speculation that the deranged metabolism of the diabetic rat liver might be due to potassium depletion; however, potassium concentration in diabetic rat liver has been found to be normal.‘22
242
WELT,
HOLLANDER,
AND BLYTHE
J. Chron. Dis. March, 1960
Potassium depletion has been shown to influence carbohydrate metabolism in animal experiments and clinical studies; however, all the findings are not consistent with those of in vitro experiments. Reduced glucose tolerance has been observed in man78 and rat.105J10Both postprandial”0 and fasting’05 liver glycogen concentrations have been found to be higher than control values in rats, a finding perhaps conflicting with the liver-slice experiments of Hastings and co-workers.n2 In the former experiments, however, there was evidence to suggest increased adrenal cortical activity which could have increased gluconeogenesis and resulted in increased liver glycogen. Liver glycogen was practically absent in rats deprived of potassium for 90 to 120 days.“O This was thought to have resulted from blocked glycogenesis due to cumulative potassium loss; however, starvation might have been the causative factor of the low liver glycogen content. Protein Metabolism.-Failure to grow is a hallmark of chronic potassium deprivation and, indeed, was one of the earliest demonstrated effects of potassium depletion. Part of the growth retardation is no doubt the result of poor dietary intake secondary to anorexia associated with potassium deprivation, but in several experiments growth failure has been shown to be a specific effect of potassium depletion.18~93J3gJ58It is not known whether this resulted specifically from disturbed protein metabolism. It has been demonstrated, however, that nitrogen balance is less positive in potassium-depleted rats than in control rats, even though nitrogen intake in the two groups is not significantly different.rs8 Growth failure is therefore due, in part at least, to derangement in protein metabolism related specifically to lack of potassium. It is not known whether the lessened positivity of nitrogen balance is the result of decreased absorption of nitrogen from the gastrointestinal tract or increased urinary nitrogen excretion secondary to either decreased anabolism or increased catabolism of protein. In man there are no convincing data that potassium depletion promotes nitrogen wasting, but there is evidence that nitrogen retention is more marked in potassium-depleted hypogonadal subjects treated with testosterone when potassium is added to the diet.lzg EFFECTS
ON MUSCLE
Skeletal Muscle Pathology.-Pathologic changes in skeletal muscle have been observed in the rat,41 dog,24o and rabbit.144 It is interesting that out of the many studies on the effects of potassium depletion in the rat, skeletal muscle lesions have been only rarely reported. Cohen, Schwartz, and Wallace4r found extensive involvement of skeletal muscle throughout the body, but particularly in the hind legs. The changes were those of Zenker’s waxy degeneration: the muscle fibers lost their cross striations and then either underwent necrosis or lost their sarcoplasm. Regeneration occurred rapidly after the administration of potassium and consisted largely of reconstitution of muscle fibers by multiplication and production of sarcoplasm on the part of the sarcolemmal cells. Similar changes in muscle have been observed in the dogz40 where muscle paralysis is a more striking feature. In rabbits in which paralysis is also a prominent accompaniment of potassium depletion, “atrophic and streaked musculature of the limbs” has been noted.144
“N::::!3’
THE CONSEQUENCES
OF POTASSIUM
DEPLETION
243
Neuromuscular Function.-Muscle weakness and paralysis occur in various clinical situations in which hypokalemia and/or potassium depletion are present, and they have been produced in experimental studies in dogsz40 and rabbits.144 Neither the incidence nor the magnitude of weakness and paralysis are apparently related to the degree of hypokalemia and/or potassium deficiency per se; in fact, they may be seen in situations in which hyperkalemia is present.64 Although the actual mechanism responsible for the paralysis remains unknown, information which is helpful in understanding why it may be present in some cases of hypokalemia and potassium depletion and absent in others has been advanced in studies of the relationship of muscle function to movement of potassium in and out of muscle in normal subjectsng and in patients with familial periodic paralysis.l18 It was found in normal subjects that maneuvers which increased extracellular potassium concentration and probably decreased or did not affect intracellular concentration, so that the ratio of intracellular to extracellular potassium concentration was probably decreased, were associated with increase in contractility of muscle and ease in depolarization by acetylcholine. These phenomena were attributed to a reduction in resting muscle membrane potential. Conversely, manipulations which probably resulted in an increased intracellular to extracellular potassium concentration ratio were associated with a decrease in ease of depolarization with acetylcholine which was attributed to an increase in the resting membrane potential. Studies on patients with familial periodic paralysis revealed that attacks of weakness which occurred spontaneously or following the administration of food, glucose, or insulin were associated with reduced plasma concentrations and increased muscle uptake of potassium as well as reduction in muscle responsiveness to nerve stimulation and acetylcholine and reduction in propagation of excitation and in contractility. Presumably, in this situation, the unresponsiveness resulted from increase in membrane potential secondary to an increased intracellular to extracellular potassium concentration ratio. On the basis of these studies, the authors postulated that muscle weakness and paralysis occur in familial periodic paralysis when the muscle membrane potential is increased as a result of increase in the ratio of intracellular to extracellular potassium concentrations effected by movement of potassium into muscle cells, and they presume that paralysis results in other situations associated with hypokalemia and/or potassium deficiency when, for various reasons, the ratio is increased. The relatively infrequent occurrence of paralysis in potassium depletion as compared to familial periodic paralysis might be a reflection of the fact that in many situations intracellular and extracellular potassium concentrations are decreased and therefore the ratio between the two tends to remain constant. These postulations are based on the assumption that increased uptake of potassium by muscle cells results in increased intracellular concentration of potassium, an assumption which is not necessarily true. Furthermore, it has been pointed out that the total concentration of potassium inside and/or outside of cells may be of less importance than the levels of ionized potassium.54
244
WELT,
Since
hypokalemia,
muscular
HOLLANDER,
in contrast
irritability,
it might
J.
.4ND BLTTHE
to hypocalcemia,
be anticipated
that
promotes tetany
Chrm. March.
decreased
Dis. 1960
neuro-
would not accompany
potassium depletion. Indeed, it has been pointed out that hypocalcemic tetany may be masked by hypokalemia and appear only when potassium stores are repleted.xO
Tetany
has been
presence77,?06~207~Z?4but for this are not clear. frequently
of ionized
depletion
calcium.
Extracellular
calcium
have
occurred,77J06J24
and
in several
there had been a recent information
regarding
reports
change
alkalosis
effects
reasons
alkalosis
levels
depressed
were
and alkalosis.
to emphasize
tetany
normalg4,206
This explana-
the need for more
of the levels of potassium,
factors,
that
for diminished
and slightly
calcium
on neuromuscular
that has been observed
with potassium
the administration
in the
The
of the cases in which
hypokalemia
other
phenomenon associated
be responsible
in many
and serves
and perhaps
interesting
following
deficiency
the extracellular
may
where
toward
the interrelated
electroencephalograms normal
been present
an oversimplification
pCOZ, pH, magnesium, A related
in potassium
that
potassium
levels of serum
tion is no doubt
however,
It has been suggested
accompanies
concentration
observed,
also in the absence77,g4,150 of hypocalcemia.
concerns
depletion,
calcium,
irritability-. abnormal
with restoration
to
of potassium.gg
EDEMd
The
association
on both clinical
of edema
in experimentally context
as well.
with
potassium
induced Kornberg
deficits
depletionz15
in man
and Endicott
has been commented
and lower animals
158described
and in a
hydrothorax,
ascites,
submucosal intestinal edema, as well as striking separation of the lobules of the pancreas in experimental potassium depletion in the rat. A positive balance of sodium
in excess
of the
negative
balance
many.14~‘5~7g~145~14g~210.212 The discrepancy there
was a negative
balances
of sodium
of increased
augmented
potassium the
excretion
appeared
the
deficit
and
been
space
reported.
early
phase
might
positive Evidence
tissue.3g,50,127~i4g,i85,236 and edema
14.15,88,96~234.256
of repletion, been
by
presented14~15~38~7g,265as well
of muscle
completely have
observed
respectively.
the loss of weight
been
been
and in one instance15
and concomitant
In
some
during
instances
to be followed
by a
corrected.38,234 ascribed
hypoalbuminemia,38,1*1,Zj6
edema disappeared by- an improvement
of acute potassium space was unaltered
has
was more
the edema including
has
and 649 mM.,
chloride
of sodium
during
instances
deficiencies,
fact that the unaccompanied
volume
has likewise
as the potassium
In some tritional
fluid
of 278 mM.
of 1,102
in the calculated
repletion
edema
diuresis
of potassium
and chloride
extracellular
as of an increase The
balance
of potassium
can be quite striking
to coexisting
were
it
not
for
nuthe
with replacement of the potassium deficit in the level of serum albumin. In one study
depletion induced by artificial hemodialysis,204 but the plasma volume was expanded.
the sucrose
It may not be too difficult to offer an explanation for the development of edema in the early phase of repletion with potassium. In this circumstance the entrance of potassium into the cells is accompanied by a release of sodium to the extracellular
fluid. This
can be likened
to the sudden
accession
of an equiva-
\‘olumr
11
xum1m 3
THE (‘ONSEC)I’EN(‘ES
01; I’OT.-\SSII~M DEPLETION
245
lent quantity of sodium from an exogenous source. If appropriate quantities of water are retained with the sodium, there is an isotonic expansion of the extracellular fluid compartment. There is frequently a lag in the dissipation of such an expansion. It is more difficult to understand the retention of sodium in excess of that which replaces potassium in the cells during the development of the depletion. This can hardly be ascribed to an increased secretion of aldosterone, since the evidence suggests that potassium depletion is associated with a diminished excretion of this hormone. 151A depressed glomerular filtration rate is sometimes associated with potassium depletion. Since there is a correlation between the filtered load of sodium and its rate of excretion in the urine, a depressed GFR might be responsible for the retention of sodium in some instances. Although there are unequivocal myocardial lesions and alterations in the ECG during potassium depletion, there is no convincing evidence that these structural and functional abnormalities eventuate in heart failure which, in turn, might promote sodium retention; neither are there obvious disturbances in those factors which are thought to stimulate “volume receptors.“23g It is possible that some specific alteration in the composition and, hence, function of the renal tubular cells is responsible for this sodium retention. A deficiency of potassium in key cells of the renal tubule may well be responsible for a more favorable competitive position of hydrogen ions vis-a-vis potassium for exchange with sodium, but this does not offer an explanation for an increased reabsorption of sodium. The avidity of potassium-depleted renal tubular cells for another cation of equal charge might somehow promote the uptake of sodium from the tubular lumen, but there are no data to support this. In fact, in contrast to other tissues there is no increase in the sodium content of the potassium-depleted kidney. Regardless of the responsible mechanism, it is clear that expansion of the extracellular fluid compartment may occur during the development of potassium depletion and in the early stages of repletion. On the other hand, the authors have not been impressed either with the frequency or the severity of this complication of potassium depletion. It would be wise, nevertheless, to bear this complication in mind whenever an increased volume of extracellular fluid may have particularly deleterious effects. REFERENCES
1.
Achor, R. W. P., and Smith, L. A.: Nutritional Deficiency Syndrome With Diarrhea Resulting in Hypopotassemia, Muscle Degeneration and Renal Insufficiency; Report of a Case With Recovery, Proc. Staff Meet. Mayo Clin. 30:207, 1955. Anderson, H. M., and Laragh, J.: Renal Excretion of Potassium in Normal and Sodium Depleted Dogs, J. Clin. Invest. 37:323, 1958. Anderson, H. M., and Mudge, G. H.: The Effect of Potassium on Intracellular Bicarbonate in Slices of Kidney Cortex, J. Clin. Invest. 34:1691, 1955. Ashford, C. A:, and Dixon, K. C.: The Effect of Potassium on the Glucolysis of Brain Tissue With Reference to the Pasteur Effect, Biochem. J. 29:157, 1935. Barrett, P. K. M., Bayliss, R. I. S., and Rees, J. R.: Conn’s Syndrome, Proc. Roy. Sot. Med. 51:720, 1958. Bartter, F. C., and Biglieri, E. G.: Primary Aldosteronism: Clinical Staff Conference at the National Institutes of Health, Ann. Int. Med. 48~8647, 1958. Bellet, S.: Clinical Disorders of the Heart Beat, Philadelphia, 1953, Lea & Febiger. Bellet, S., Stieger, W. A., Nadler, C. S., and Gazes, P. C.: Electrocardiographic Patterns i;b5Hypopotassemia: Observations on Seventy-nine Patients, Am. J. M. SC. 219:542,
246 9. 10. 11. 12.
WELT,
HOLLANDER,
AND BLYTHE
J. Chron. Dis. March, 1960
Berliner, R. W.: Renal Secretion of Potassium and Hydrogen Ions, Fed. Proc. 11:695, 1952. Berliner, R. W., Kennedy, T. J., J r., and Orloff, J.: Relationship Between Acidification of the Urine and Potassium Metabolism, Am. J. Med. 11:274, 1951. Berliner, R. W., Kennedy, T. J., Jr., and Orloff, J.: Factors Affecting the Transport of Potassium and Hydrogen Ions by the Renal Tubules, Arch. internat. pharmacodyn. 97:299, 1954. Berliner, R. W., Levinsky, N. G., Davidson, D. G., and Eden, M.: Dilution and Concentration of the Urine and the Action of Antidiuretic Hormone, Am. J. Med. 24:730, 1958.
13.
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z%:r ‘: 223. 224. 225. 226.
227. 228.
229.
THE CONSEQLENCES
OF POTASSIUM
DEPLETION
253
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244. 245.
246. 247. 248. 249. 2.50.
251.
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