The consequences of potassium depletion

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, ti...

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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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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.

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Bergstrom., W. H., and Wallace, W. M.: Bone as a Sodium and Potassium Reservoir, J. Clm. Invest. 33:867, 1954. 14. Black, D. A. K., and Mime, M. D.: Experimental Potassium Depletion in Man, Clin. SC. 11:397. 1952. 15. Blahd, W. H., and Bassett, S. H.: Potassium Deficiency in Man, Metabolism 2:218, 1953. 16. Boyer, P. D., Lardy, H. A., and Phillips, P. H.: The Role of Potassium in Muscle Phosphorylations, J. Biol. Chem. 146:673, 1942. 17. Boyer, P. D., Lardy, H. A., and Phillips, P. H.: Further Studies on the Role of Potassium and Other Ions in the Phosphorylation of the Adenylic System, J. Biol. Chem. 149:529, 1943. 18. Brokaw, A.: Renal Hypertrophy and Polydipsia in Potassium-deficient Rats, Am. J. Phvsiol. 172:333. 1953. 19. Brooks, C. McC., Hoffman, B. F., and Suckling, E. E.: Excitability of the Heart, New York, 19.55, Grune & Stratton, Inc. 20. Brooks, R. V., McSwiney, R. R., Prunty, F. T. G., and Wood, F. J. Y.: Potassium Deficiency of Renal and Adrenal Origin, Am. J. Med. 23:391, 1957. 21. van Buchem, F. S. P., Doorenbos, H., and Elings, H. S.: Primary Aldosteronism Due to Adrenocortical Hyperplasia, Lancet 2:335, 1956. 22. van Buchem, F. S. P., Doorenbos, H., and Elings, H. S.: Conn’s Syndrome, Caused by Adrenocortical Hyperplasia. Pathogenesis of the Signs and Symptoms, Acta endocrinol. 23:313, 1956. 23. Burnell, J. M., and Scribner, B. H.: Serum Potassium Concentration as a Guide to Potassium Need, J.A.M.A. 164:959, 1957. 24. Burnell, J. M., Villamil, M. F., Uyeno, B. T., and Scribner, B. H.: The Effect in Humans of Extracellular pH Change on the Relationship Between Serum Potassium Concentration and Intracellular Potassium, J. Clin. Invest. 35:935, 1956. 25. Burnett, C. H,, Burrows, B. A., and Commons, R. R.: Studies of Alkalosis. I. Renal Function Durmg and Following Alkalosis Resulting From Pyloric Obstruction, J. Clin. Invest. 29:169, 1950. 26. Burnett, C. H., Burrows, B. A., Commons, R. R., and Towery, B. T.: Studies of Alkalosis. II. Electrolyte Abnormalities in Alkalosis Resulting From Pyloric Obstruction, J. Clin. Invest. 29:175, 1950. 27. Burnett. C. H.. and Williams. T. F.: An Analvsis of Some Features of Renal Tubular Dysfunction, A.M.A. Arch. Int. Med. 102:881, 1958. 28. Butcher, W. A., Wakim, G. K., Essex, H. E., Pruitt, R. D., and Burchell, H. B.: The Effects of Changes in Concentration of Cations on the Electrocardiogram of the Isolated Perfused Heart, Am. Heart J. 43:801, 19.52. 29. Calkins, E., and Taylor, I. M.: Some Observations on the Interrelationship of Potassium Metabolism and Carbohydrate Metabolism in the Isolated Rat’s Diaphragm, in Najjar, V., editor: A Symposium on the Clinical and Biochemical Aspects of Carbohydrate Utilization in Health and Disease, Baltimore, 1952, Johns Hopkins Press. Tumour With 30. Campbell, C. H., Nicolaides, N., and Steinbeck, A. W.: Adrenocortical Hypokalaemia and Flaccid Muscle Paralysis, Lancet 2:553, 1956. 31. Cannon, P. R., Frazier, L. E., and Hughes, R. H.: Influence of Potassium on Tissue Protein Synthesis, Metabolism 1:49, 1952. 32. Cannon, P. R., Frazier, L. E., and Hughes, R. H.: Sodium as a Toxic Ion in Potassium Deficiency, Metabolism 2:297, 1953. 33. Carone, F. A., and Cooke, R. E.: Effect of Potassium Deficiency on Gastric Secretion in Rat, Am. J. Physiol. 172:684, 1953. 34. Castleman, B., editor: Case Records of the Massachusetts General Hospital. #40081, New England J. Med. 2.50:334, 1954. 3.5. Castleman, B., editor: Case Records of the Massachusetts General Hospital. f41171, New England J. Med. 252:723, 1955. 36. Castleman, B., editor: Case Records of the Massachusetts General Hospital. #44491, New England J. Med. 259:1128, 1958. 37. Chalmers, T. M., Fitzgerald, M. G., James, A. H., and Scarborough, H.: Conn’s Syndrome With Severe Hypertension, Lancet 1:127, 1956. 38. Cheek, D. B.: Total Body Chloride of Children in Potassium Deficiency and Under Circumstances of Poor Nutrition, Pediatrics 14:193, 1954. 39. Cheek, D. B., and West, C. D.: Alterations in Body Composition With Sodium Loading

Volun1e

11

Numb er 3

40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

: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,

248 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85.

86. 87. 88. 89. 90. 91. 92. 93. 94. 9.5. 96. 97. 98. 99. 100. 101. 102.

WELT,

Eckel,

HOLLANDER,

AND

BLE’THE

J. Chron. Dis. March, 1960

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Frenkel, M., Groen, J., and Willebrand, A. F.: Low Serum Potassium Level During Recovery From Diabetic Coma. With Special Reference to Its Cardiovascular Manifestations, Arch. Int. Med. 80:728, 1947. Friedman, M.! Rosenman, R. H., and Freed, S. C.: The Depressor Effect of Potassium Deprivation on the Blood Pressure of Hypertensive Rats, Am. J. Physiol. 167:457, 1951. Fuhrman, F. A.: Glycogen, Glucose Tolerance and Tissue Metabolism in Potassium Deficient Rats, Am. J. Physiol. 167:314, 1951. Gamble, A. H., Wiese, H. F., and Hansen, A. E.: Marked Hypokalemia in Prolonged Diarrhea; Possible Effect on Heart, Pediatrics 1:58, 1948. Gamble, J. L., Fahey, K. R., Appleton, J., and MacLachlan, E.: Congenital Alkalosis With Diarrhea, J. Pediat. 26:509, 194.5. Gardner, L. I., MacLachlan, E. A., and Berman, H.: Effect of Potassium Deficiency on Carbon Dioxide, Cation, and Phosphate Content of Muscle, J. Gen. Physiol. 36:153, 19.52. Gardner, L. I., MacLachlan, B. A.! Terry, M. L., McArthur, J. W., and Butler, A. M.: Chloride Diarrhea and Systemic Alkalosis in Potassium Deficiency, Fed. Proc. 8:201, 1949. Gardner, L. I., Talbot, N. B., Cook, C. D., Berman, H., and Uribe, C.: The Effect of Potassium Deficiency on Carbohydrate Metabolism, J. Lab. & Clin. Med. 35:592, 1950. Giebisch, G., Benger, L., and Pitts, R. F.: The Extrarenal Response to Acute Acid-base Disturbances of Respiratory Origin, J. Clin. Invest. 34:231, 1955. Giebisch, G., and Lozano, R.: The Effects of Adrenal Steroids and Potassium Depletion on the Elaborations of an Osmotically Concentrated Urine, J. Clin. Invest. 38:843, 1959. Giebisch, G., Macleod, M. B., and Pitts, R. F.: Effect of Adrenal Steroids on Renal Tubular Reabsorption of Bicarbonate, Am. J. Physiol. 183:377, 1955. van Goidsenhoven, G. M.-T., Gray, 0. V., Price, A. V., and Sanderson, P. H.: The Effect of Prolonged Administration of Large Doses of Sodium Bicarbonate in Man, Clin. SC. 13:383, 1954. Goodof, I. I., and MacBryde, C. M.: Heart Failure in Addison’s Disease With Myocardial Changes of Potassium Deficiency, J. Clin. Endocrinol. 4:30, 1944. Gottschalk, C. W., and Mylle, M.: Micropuncture Study of the Mammalian IJrinary Concentrating Mechanism: Evidence for the Countercurrent Hypothesis, Am. J. Physiol. 196:927, 1959. Gottschalk, C. W., Mylle, M., Winters, R. W., and Welt, L. G.: Micropuncture Study of the Osmolahty of Renal Tubular Fluid in Potassium-depleted Rats, J. Clin. Invest. 37 :898, 19.58. Grob, p:, Johns, R. J., and Liljestrand, A.: Potassium Movement in Patients With Famlhal Periodic Paralysis. Relationship to the Defect in Muscle Function, Am. J. Med. 23:356, 1957. Grob, D., Liljestrand, A., and Johns, R. J.: Potassium Movement in Normal Subjects. Effect on Muscle Function, Am. J. Med. 23:340, 1957. Gropper, A. L.: Acute Renal Failure Responding to Potassium Replacement Therapy, Am. J. Med. 24:153, 1958. Hansen, J. D. L., and Brock, J. F.: Potassium Deficiency in the Pathogenesis of Nutritional Oedema in Infants, Lancet 2:477, 1954. Hastings, A. B., Renold, A. E., and Ching-Tseng Teng: Effects of Ions and Hormones on Carbohydrate Metabolism, in Pincus, G., editor: Recent Progress in Hormone Research, Vol. XI, New York, 1955, Academic Press, Inc., p. 381. Hegnauer, A. H.: The Effect of a Low Potassium Diet and of Desoxycorticosterone Acetate on the Cation Content of Rat Erythrocytes and Muscle, J. Biol. Chem. 150:353, 1953. Hellem, A. J.: Primary Aldosteronism (Report of a Case), Acta med. scandinav. 155:271, 1956. Hellems, H. K., Regan, J. J., and Talmers, F. N.: Influence of Acety! Strophanthidin on Myocardial Electrolyte Exchange, J. Clin. Invest. 34:915, 19.55. Henderson, C. B.: Potassium and the Cardiographic Changes in Diabetic Acidosis, Brit. Heart J. 15:87, 1943. Heppel. L. A.: The Electrolytes of Muscle and Liver in Potassium-depleted Rats, Am. J. Physiol. 127:385, 1939. Heppel, L. A.: The Diffusion of Radioactive Sodium Into the Muscles of Potassium-depleted Rats, Am. J. Physiol. 128:449, 1939-1940. Herndon, E. G., Jr:, Rubini, M. E., and Meroney, W. H.: Protein .i\nabolism in Potassium Depletion, Clm. Res. Proc. 6:262, 1958. Hewlett, J. S., McCullagh. E. P, Farrell, G. I,., LIustan, H. P., Poutasse, E. F., and Proudfit, W. L.: Aldosterone-producing Tumors of the Adrenal Gland: Report of Three Cases, J.A.M.A. 164:719, 1957. Hickam, J. B., Wilson, W. P., and Frayser, Ii.: Observation on the Early Elevation of Serum Potassium During Respiratory Alkalosis, J. Clin. Invest. 35:601, 1956.

250 132 133. 134. 135. 136.

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AND BLYTHE

J. Chron. Dis. March, 1960

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“Nizr‘3 163.

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Levitt, M. F., Turner, L. B., Sweet, A. Y., and Pandiri, D.: The Response of Bone, Connective Tissue, and Muscle to Acute Acidosis, J. Clin. Invest. 35:98, 1956. 164. Liebow, A. A., McFarland, W. J., and Tennant, R.: The Effects of Potassium Deficiency on Tumor-bearing Mice, Yale J. Biol. & Med. 13:523, 1941. 165. Lown, B.: Potassium and Digitalis, in Dimond, E. G., compiler and editor: Digitalis, Springfield, Ill., 1957, Charles C Thomas, Publisher. 166. Lown, B., and Levine, H.: Atria1 Arrhythmias, Digitalis and Potassium, New York, 1958, Lundsberger Medical Books, Inc. 167. Luft, R., Ringertz, N., and Sjogren, B.: Two Cases of Cryptogenetic Hypokalemia With Pathological Anatomical Findings, Separatum acta endocrinol. 7:196, 1951. 168. McAllen, P. M.: The Electrocardiogram Associated With Low Levels of Serum Potassium, Brit. Heart J. 13:159, 1951. 169. McAllen, P. M.: Myocardial Changes Occurring in Potassium Deficiency, Brit. Heart J. 17:s. 1955. 170. MacPherson, C. R.: Myocardial Necrosis in the Potassium Depleted Rat: A Reassessment, Brit. J. Exper. Path. 37:279, 1956. Hypomagnesemia, Alkalosis 171. Mader, I. J., and Iseri, L. T.: Spontaneous Hypopotassemia, and Tetany Due to Hypersecretion of Corticosterone-lrke Mineralocorticoid, Am. J. Med. 19:976, 1955. Renal Disease, Quart. J. Med. 172. Mahler. R. F, and Stanbury, S. W.: Potassium-losing 25:21, 1956. 173. Manitius, A., Beck, D:, Levitin, H., and Epstein, F. H.: Observations on the Chemical Composition of Kidney Tissue in Potassium Depletion and Nephrocalcinosis, Clin. Res. 7:275, 1959. 174. Meyer, J. H., Grunert, R. R., Zepplin, M. T., Grummer. R. H., Bohstedt, G., and Phillips, P. H.: Effect of Dietary Levels of Sodium and Potassium on Growth and on Concentrations in Blood Plasma and Tissues of White Rat, Am. J. Physiol. 162:182, 1950. 175. Mime, M. D., and Muehrcke, R. C.: Potassium Deficiency and the Kidney, Brit. M. Bull. 13:15, 1957. 176. Milne, M. D., Muehrcke, R. C., and Aird, I.: Primary Aldosteronism, Quart. J. Med. 26:317, 19.57. 17Aa. Morrison, A. B.: Personal Communication. 177. Mudge, G. H.: Clinical Patterns of Tubular Dysfunction, Am, J. Med. 24:785, 1958. 178. Mudge, G. H., and Beskind, H.: Effect of Potassium Deficiency on Renal Tubular Reabsorption and Assimilation of Glucose, Bull. Johns Hopkins Hosp. 104:252, 1959. 179. Mudge, G. H., Foulks, J., and Gilman, A.: The Renal Excretion of Potassium, Proc. Sot. Exper. Biol. & Med. 67:545, 1948. 180. Mudge, G. H., and Hardin, B.: Response to Mercurial Diuretics During Alkalosis: A Comparison of Acute Metabolic and Chronic Hypokalemic Alkalosis in the Dog, J. Clin. Invest. 35:155, 1956. 181. Mudge, G. H., and Vislocky, K.: Electrolyte Changes in Human Striated Muscle in Acidosis and Alkalosis, J. Clin. Invest. 28:482, 1949. 182. Muehrcke, R. C., and Bonting, S. L.: Electronmicroscopic and Ultramicrobiochemical Studies of the Potassium-depleted Kidney, Clin. Res. 6:413, 1958 (Abstr.). 183. Muehrcke, R. C., and Mime, M. D.: Primary Hyperaldosteronism, Long-standing Potassium Depletion and Pyelonephritis! Clin. Res. Proc. 5:190, 1957 (Abstr.). 184. Mulinos, M. G., Spingern, C. L., and Lojkm, M. E.: A Diabetes Insipidus-like Condition Produced by Small Doses of Desoxycorticosterone Acetate in Dogs, Am. J Physiol. 135:102, 1941. 185. Muntwyler, E., and Griffin, G. E.: Effect of Potassium on Electrolytes of Rat Plasma and Muscle, Am. J. Physiol. 193:563, 1951. 186. Muntwyler, E., and Griffin, G. E.: Creatinine Clearance in Normal and Potassium Deficient Rats, Am. J. Physiol. 173:145, 1953. 187. Muntwyler, E., and Griffin, G. E.: Tissue Electrolyte Content of Potassium and Proteindeficient Rats, Proc. Sot. Exper. Biol. & Med. 89:349, 1955. 188. Muntwyler, E., Griffin, G. E., and Arends, R. L.: Muscle Electrolyte Composition and Balances of Nitrogen and Potassium in Potassium-deficient Rats, Am. J. Physiol. 174:283. 1953. 189. Muntwyler, E., Griffin, G. E., Samuelsen, G. S., and Griffin, L. G.: The Relation of the Electrolyte Composition of Plasma and Skeletal Muscle, J. Biol. Chem. 185:525, 1950. 190. Newton, M., Lazcano, F., Blythe, W. B., and Welt, L. G.: Unpublished Observations. 190a. Oliver, J.: New Directions in Renal Morphology: Method, Its Results and Its Future, Harvey Lect. 40:102, 1944-1945. 191. Oliver, J., MacDowell, M., Welt, L. G., Holliday, M. A., Hollander, W., Jr., Winters, R. W., Williams, T. F., and Segar, W. E.: The Renal Lesions of Electrolyte Imbalance. I. The Structural Alterations in Potassium-depleted Rats, J. Exper. Med. 106:563, 1957. 192. Orent-Keiles, E., and McCollum, E. V.: Potassium in Animal Nutrition, J. Biol. Chem. 140:337, 1941.

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207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222.

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Orloff, J., Kennedy, T. j., Jr., and Berliner, R. W.: The Effect of Potassium in Nephrectomized Rats With Hypokalemic Alkalosis, J. Clin. Invest. 32:538, 1953. Pearse, A. G. E., and MacPherson, C. R.: Renal Histochemistry in Potassium I)epletion, J. Path. & Bact. 75:69, 1958. Perdue, H. S., and Phillips, P. H.: Effects of Deficiencies of Sodium and Potassium 011 Motility of Intestine of Rat, Proc. Sot. Exper. Biol. & Med. 80:248, 1952. Perdue, H. S., and Phillips, P. H.: Effect of High Fat Diet on the Potassium Deficiency Syndrome in the Rat, Proc. Sot. Exper. Biol. & Med. 81:405, 1952. Perdue, H. S., and Phillips, P. H.: Stimulation of Peristalsis in Potassium Deficient Rat by Acetyl-&methylcholine, Proc. Sot. Exper. Biol. & Med., 81:438, 1952. Perera, G. A.: Depressor Effects of Potassium Deficient Diets in Hypertensive Man, J. Clin. Invest. 32:633, 1953. Perkins, J. G., Petersen, A. B., and Riley, J. A.: Renal and Cardiac Lesions in Potassium Deficiency Due to Chronic Diarrhea, Am. J. Med. 8:115, 1950. Peschel, E., Black-Schaffer, B., and Schlayer, C.: Potassium Deficiency as Cause of Socalled Rheumatic Heart Lesions of Adaptation Syndrome, Endocrinology 48:399, 1951. Pitts, R. F.: Mechanisms for Stabilizing the Alkaline Reserves of the Body, Harvey Lect. 48:172, 1952-1953. Plum, F., and Dunning, M. F.: Enema-induced Potassium Loss in Patients With Diseases of Spinal Cord Roots, Tr. ,4m. Neurol. A. 80:219, 1955. Pollak, V. E., Flagg, G. W., Muehrcke, R. C., and Kark, R. M.: Potassium Depletion Following Self-induced Diarrhea and Vomiting, Treated by Prolonged Psychotherapy, Clin. Res. Proc. 5:194, 1957. Prudden, J. F., Danzig, L. E., and Stirman, J. A.: The Effect of Acute Potassium Depletion on the Functional Compartmentalization of Water, Surg. Gynec. & Obst. 102:553, IQ56 _,_-. Ragan, C., Ferrebee, J. W.., Phyfe, P:, Atchley, D. W., and Loeb, R. F.: A Syndrome of Polydipsia and Polyurla Induced m Normal Animals by Desoxycorticosterone Acetate, Am. I. Phvsiol. 131:73. 1940. Rapoport,“S., DLdd, K., Claik, M., and Syllm, I.: Post-acidotic State in Infantile Diarrhea: Symptoms and Chemical Data. Post Acidotic Hypocalcemia and Associated Decreases in Levels of Potassium, Phosphorus, and Phosphatase in Plasma, Am. J. Dis. Child. 73:391, 1947. Ravdin, I. S., Aronson, P. R., and Yules, J. H.: Complications of the Diuretic Phase of Lower Nephron Nephrosis. Report of a Case Manifesting Tetany, New England J. Med. 244:830, 1951. Rector, F. C., Seldin, D. W., and Copenhaver., J. H.: The Mechanism of Ammonia Excretion During Ammonium Chloride Acidosis, J. Clin. Invest. 34:20, 195.5. Rector, F. C., Jr., Seldin, D. W., Roberts, A. D., Jr., and Copenhaver, J. H.: Relation of Ammonia Excretion to Urine DH. Am. 1. Phvsiol. 179:353. 1954. Reimes, A., Schoch, H. K., and Nkwburgh,-L. fi.: Certain Aspects of Potassium Metabohsm, J. Am. Dietet. A. 27:1042, 1951. Reinecke, R. M., Holland, C. R., and Stutzman, F. L.: Homeostasis of Potassium in the Extracellular Fluid of the Dog During Removal by Vivodialysis, Am. J. Physiol. 156:290, 1949. Relman, A. S., and Schwartz: W. B.: The Effect of DOCA on Electrolyte Balance in Normal Man and Its Relation to Sodium Chloride Intake. Yale 1. Biol. & Med. 24:540. 1951-1952. Relman, A. S., and Schwartz, W. B.: The Nephropathy of Potassium Depletion. A Clinical and Pathological Entity, New England J. Med. 255:195, 1956. Relman. A. S.. and Schwartz. W. B.: Electrolvte Balance and Acid-base Metabolism in Primary Aldosteronism, j. Clin. Invest. 38:923, 1957. Relman, A. S., and Schwartz, W. B.: The Kidney in Potassium Depletion, Am. J. Med. 24:764, 1958. Reynolds! T. B., Martin, H. E., and Homann, R. E.: Serum Electrolytes and the Electrocardiogram, Am. Heart J. 42:671, 1951. Rhodin, J.: Electron Microscopy of the Kidney, Am. J. Med. 24:661, 1958. Richter, H. S.: Action of Antidiuretic Hormone in Potassium-depleted Rats; Relation to Aldosteronism, Proc. Sot. Exper. Biol. & Med. 97:141, 1958. Roberts, K. E., and Pitts, R. F.: The Effects of Cortisone and Desoxycorticosterone on the Renal Tubular Reabsorption of Phosphate and the Excretion of Titratable Acid and Potassium in Dogs, Endocrinology 52:324, 1953. Roberts, K. E., Randall, H. T., Philbin, P., and Lipton, R. : Changes in Extracellular water and Electrolytes and the Renal Compensation in Chronic Alkalosis, as Compared to Those Occurring in Acute Alkalosis, Surgery 36:599, 1954. Roberts, K. E., Randall, H. T., Sanders, H. L., and Hood, M.: Effects of Potassium on Renal Tubular Reabsorption of Bicarbonate, J. Clin. Invest. 34:666, 1955. Robinson, J. G., Edwards, J. E., Higgins, G. M. and Burchell, H. B.: Effect of Digitalis

z%:r ‘: 223. 224. 225. 226.

227. 228.

229.

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