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Resting Skeletal Muscle Membrane Potential as

an Index of Uremic Toxicity: A PROPOSED NEW

METHOD TO ASSESS ADEQUACY OF

HEMODIALYSIS

James R. Cotton, … , Norman W. Carter, James P. Knochel

J Clin Invest. 1979;63(3):501-506. https://doi.org/10.1172/JCI109328.

Electrochemical disturbances of skeletal muscle cells in untreated uremia are characterized by an increase in the intracellular sodium and chloride content, a decrease in intracellular potassium, and a low resting membrane potential. In this study, we have reexamined the foregoing and, in addition, have examined the effects of hemodialysis. Three groups of patients were studied. In the first group of 22 uncomplicated uremic patients, whose

creatinine clearance (Ccr) ranged from 2 to 12 cm3/min per 1.73 m2, resting transmembrane potential difference (Em) of skeletal muscle cells was measured. In each of the nine patients whose Ccr ranged between 6.3 and 12 cm3/min, the Em was normal (i.e., −90.8±0.9 mV, mean±SEM). However, as Ccr dropped below 6.3 cm/min, the Em became progressively reduced and assumed a linear relationship with the Ccr.

In the second study, nine individuals with end-stage renal disease, whose mean Ccr was 4.3 cm3/min, underwent measurement of Em and intracellular electrolyte concentration before and after 7 wk of hemodialysis. Before dialysis, the Em was −78.5±2.1 mV, intracellular sodium and chloride were elevated, and the intracellular potassium was reduced. After 7 wk of hemodialysis the Em rose to −87.8±1.3 mV, and the intracellular sodium, chloride, and potassium became normal.

In the third study, seven patients who were stable on 6-h thrice-weekly dialysis were studied before and after reduction of […]

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Resting Skeletal Muscle Membrane Potential

as an

Index of Uremic Toxicity

A PROPOSED NEW METHOD TO ASSESS ADEQUACY OF HEMODIALYSIS

JAMESR. COTTON, TERRYWOODARD,NORMANW.CARTER, andJAMES P. KNOCHEL,

Veterans Administration Medical Center, and Depatrtment of Internal Medicine, University of Texas Health Science Centter, Dallas, Texas 75235

A BS TRAC T Electrochemical disturbances of skele-tal muscle cellsin untreated uremia are characterized by an increaseintheintracellular sodium and chloride content, a decrease in intracellular potassium, and a

low restingmembranepotential. In this study, we have

reexamined the foregoing and, in addition, have

examined theeffectsofhemodialysis. Three groups of patients were studied. Inthe first group of22

uncom-plicated uremic patients, whose creatinine clearance

(Ccr) raniged from 2 to 12 c1m3/111in1 per 1.73 1in2,

rest-ing transmlembrane potential differeniee(Em) of skeletal

mutsclecells was measured.Ineach of theninepatients whoseCerrangedbetween 6.3 an(l 12Cm3/min, the Em wasnonral(i.e., -90.8+0.9mV, mean±SENI). However, as Ccr dropped below 6.3 cm/min, the Em became

progressively reduced and assumed a linear relation-ship with the Ccr.

In the second study, nine individuals with end-stage renaldisease, whose mean Ccr was 4.3 cm3/min,

underwent measurement ofEmand intracellular elec-trolyte concentration before and after 7 wk of

hemo-dialysis. Before dialysis, the Em was -78.5+2.1 mV,

intracellular sodium and chloride were elevated, and the intracellular potassium was reduced. After 7 wk

ofhemodialysistheEmrose to -87.8+1.3mV, and the intracellular sodium, chloride, and potassium became normal.

Inthe thirdstudy,sevenpatients who were stable on

6-h thrice-weekly

dialysis

were

stnidied

before and af-terreduction ofdialysis to6h twice weekly. In those individuals whose Em remained normal after 6 wk, dialysis time was reduced further. On thrice-weekly

This material was presented in preliminary form at the Annual Meeting of the American Society of Nephrology, Washington, D. C.,1977.

Receivedforpublication3Marchl1978acndin revisedform

6Novermber1978.

dialysis the Em was -91.2±1.0 mV. With reduced dialysis, the Em fell to -80.1+0.8 mV (P<0.001). In

each case, the Em became abnormal beforesignificant

signs or symptoms ofuremia were noted. These find-ings demonstrate that end-stage renal disease is as-sociated with serious electrochemical changes in the muscle cell which are reversed by hemodialysis and recur when dialysis time is reduced. Thus, serial

ob-servations of muscle Em maybeapotentially powerful

tool to assess adequacy of dialysis therapy.

INTRODUCTION

Previous studies from this laboratory have shown that the resting transmembrane potential differenice (Em)' of skeletal muscle cells is abnormally low in pa-tients with end-stage renal disease (1, 2). In each

in-stance, the low Em was associated with abnormalities

of cellularcomposition, thus suggestingcellularinjury. These include elevated cellular concentrations of sodium and chloride, and reduced potassium. In our ex-perience, these findings occur more consistently than

corresponding chemical derangementsoferythrocytes

(3) or leukocytes (4) in uremia. Welt et al. could

identify

this chemical alteration of erythrocyte com-positioninonly 25% of patients with uremia (3). Thus, the uniform consistency of electrochemical derange-ments in uremic muscle suggests that this tissue will more reliably mirror impairment of cellular function in uremia.

We assume that at least part of the Em of normal

muscle cells results from active sodium transport.

Al-though the reason why the Em is abnormally low in

uremia isnotclear, it seems conceivable that defective

IAbbreviationts used in this paper: Cer, creatinine

(3)

sodium transport could beatleastpartially responsible and, further, that this energy-using process might be suppressed by uremic toxins. If this is the case, ade-quate removal of the toxins by dialysis should restore the Em to normal, as well as correct the ionic dis-turbances.

In this report, we have confirmed the previously described electrochemical disturbances of the uremic muscle cell. We now show that hemodialysis can ef-fectively repair these disturbances.It isof interest that once the Em has been corrected, decreasing the frequency of hemodialysis causes a relapse of cellular injury, which suggests that the Em may be a tool to assess adequacy of dialysis therapy.

METHODS

Patients were selected from the Renal Clinic ordialysis pro-gram at the DallasVeterans Administration Hospital. Those

individuals with diabetes mellitus, active infections,

malig-nancy,endocrine derangements, orotherconcurrent serious illnesses were excluded. Theprotocol was approved bythe HumanStudiesCommittee, andinformedwrittenconsent was

obtainedonallstudysubjects.

29patientswith chronic renal failurewere separated into

threegroups. Group Iincluded22patients withchronic renal failure who had various levels of residual renal function. Endogenous creatinine clearance (Ccr) was determined by conventional methodsononeormore 24-hurinecollections. Therestingmuscle membrane potential wasmeasuredupon

completion of the Ccr procedure. All values for Ccr were

expressedascm3/minper 1.73 m2body surfacearea. Group II included nine patients from Group I who were studied immediately before chronic dialysis therapy was

initiated andagainafter7wkofhemodialysis.Each patient

un-derwentmeasurementofEmandCcr. In fiveof thenine, a

sample of skeletal muscle was obtained by needle biopsy from the lateral thigh forquantitationofNa,K,and Clcontent

by methods previously described (2).After 7 wkonstandard hemodialysis(6 h thriceweeklyon a 1.0-M2 coilora 1.3-M2 hollowfiberdialyzer),the patientswereadmittedtothe Met-abolic Unit where thestudies wererepeated. Em and skele-talmuscle electrolytemeasurements were made 48-72 h after

theprevious dialysis.

Group III included seven patientsselected fromourchronic hemodialysis population. Each had been on dialysis from6

to36mo.Theyhad noabnormalitiesother thanthoseusually

seeninchronically dialyzedpatients. Inthis group, Ccrwas

determinedon 48-72 urinecollections obtained betweentwo

dialyses.Serum creatinine wasdeterminedimmediatelyafter

andbeforethenextdialysis. Theaverageof thesetwovalues

wasusedtocalculate theCcr.Throughoutthisstudy,sixofthe patients weredialyzedwith a1.3-M2 hollow fiberdialyzerand one with a1.0-M2coil.Each patientingestedadiet containing 1g/kgofhighbiological value protein. Their intake was

esti-mated byaresearch dietitian from adaily food log kept bythe patients. The Em was not measured soonerthan 66h after their lastdialysis.The initial measurementsweremade while patients were maintained on 6h thrice-weekly

hemo-dialysis. The dialysis time was then reduced to 6h twice weekly. The Em measurements were repeated

after 6wk on reduced dialysis. If the membrane poten-tial remained normal at 6 wk, the dialysis time was

further reduced in stepwise fashion every 6 wk until the membranepotentialbecameabnormally low.

Resting Em was measured directly in the anterior tibial muscle by the same technique reported previously from this laboratory (1, 2), except that for this study we employed a Soltec Rinkidinki chart recorder (Soltec Corp., Sun Valley,

Calif.)and aKeithlyElectrometer (Keithley Instruments, Inc.,

Cleveland,Ohio) instead of an oscilloscope. This modification

substantially improved the ease and reproducibility with

which membranepotential could be determined.

5-15 individual muscle fiber potentials were recordedin

eachpatient. Thevalues reportedherein represent an average

of all individual fiber potentials from each patient. 23 healthy subjects underwent Em measurements to serve as

normal controls. Theirmean Em was -90.8±0.9 mV (Mean ±SEM).TheappropriateStudent'sttest wasused for analysisof

statisticalsignificance.

RESULTS

Todetermine reproducibility of single fiber potentials, data were analyzed from eight patients in whom two

electrodeswereused duringeachprocedure (Table I).

The number ofsingle fiber potentials ranged between 5 and 14. Ascompared by the unpaired t test, the aver-agepotentials determined fromeach set of singlefiber potentials in any given patient were not significantly different. This reproducibilitywasevident whetherthe patients were untreated or treated by hemodialysis. Therangeof individual musclefiber potentials during

each of these studies isshown in Fig. 1.

Observations fromGroupIareshownin Fig. 2. Each

TABLE I

Statistical Analysis of Individual Fiber Potentials

Numberof Average

Patient Electrode potentials Em SD

Uremic 1 A 8 71.2 4.3 B 13 73.4 8.7

2 A 4 80.7 1.4 B 6 78.4 2.5

3 A 12 75.3 2.8

B 5 75.9 0.8 4 A 13 76.2 3.9 B 7 76.0 6.4

Dialyzed 5 A 12 92.4 5.7

B 11 92.4 3.1

6 A 8 99.0 8.5

B 9 88.6 6.6

7 A 11 83.6 3.9 B 7 90.0 8.5

8 A 14 91.4 4.3 B 13 90.8 7.6 This table illustrates data derived from individual fiber

potentials shown in Fig. 1. The average potentials derived from electrodes A and B in any given patient were not

significantlydifferent from one another.

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AB AB ABA B ABA BA B A B

1 2 3 4 5 6 7 B

UREMIA HEMODIALYZED

TABLE IL

Muscle Cotmipositionibeforeatndafter 7twk ofDialysi.s

[Na]' [Cl]i* [K] ilneqiliter itntracellular H1O

Normal subjects 11±1.4 4.4+0.1 155±4.3 Before dialysis 26+4.9 4.8+0.4 147+3.1 After dialysis 14+3.1 3.5±0.5 155±4.9

P+ <0.01 <0.05 <0.01

*

[Cl]i,

intracellular chloride

concentration;

[K]',

intracellular

potassium concentration.

t Statistical analysis by paired Student's t test of values obtained before and after dialysis.

FIGURE 1 Individual muscle fiberpotentials obtained by the

use oftwodifferent electrodes duringagiven procedure on

four untreated (0) patients and four after at least 6 wk of hemodialysis (0). Separate electrodesaredesignatedAandB

under theirrespectivevalues. The electrode values shownin this figurearethe sourceof derived datainTableI.

patientwhose Ccrwasbetween 6.3 and 12cm3/min had

a normal Em. In contrast, those whose Ccr was <6.3

cm3/min had an abnormally low Em. In this latter group, the Em bore a linear relationship to the Ccr

(r =0.83; Em =69.4+2.2 Ccr; P<0.001). Although difficult to express in quantitative terms, there

ap-peared to be a relationship between the presence of

uremicsymptomsandanabnormallylow Em.Eightof

theninepatients withanormalEmwereasymptomatic. On the other hand, 3 ofthe 13 with a low Em were

clinicallyuremic.Of the remaining10,9complainedof

some symptoms compatible with end-stage renal

disease; primarilythose ofgeneralmalaiseandfatigue.

In Group II, the patients had a mean Ccr of 4.3

cm3/min per 1.73 M2. Eight of the nine patients had

100-90

> 80

E*

70-E w

60

o

0 1 2 3 4 5 6 7 8 9 10 1 12

CREATININE CLEARANCE (crn/min/1.73 m2) FIGuRE2 Skeletal muscle Em measurements in untreated patients at various stages of chronic renal failure. 25 Em

measurements weremade in22patients,2having more than one Emas theirrenal function deteriorated. As theCcr fell below6.3cm3/min, theEmbecame reduced andassumed a linearrelationship to the Ccr(r=0.83; Em=69.4+2.2Ccr; P<0.001). The shaded area represents the mean-SD of our normal controls (-90.8+4.2 mV).

symptoms of advanced renal failure; frankuremiawas

presentinthree, and fatigue and malaiseinfive of the

remaining six. Five patients underwentpercutaneous

muscle biopsy for determination of muscle electrolytes.

Data on muscle composition are shown in Table II.

These findings were similarto those madepreviously in end-stage renal disease; i.e., intracellular sodium

and chloride wereincreased,and intracellular potassium was reduced. After 7 wk of hemodialysis, intracellular

electrolyteconcentrationswerenormal.Fig.3shows the

results of theEmmeasurementsbefore and after 7 wk of

hemodialysis. Eightof theninepatients hadanabnormal Embeforedialysis,andineach,the Emroseinresponseto

hemodialysis. After dialysis,Eminoneindividualrose,

but did notachieve a normal value. All nine patients wereasymptomaticattheend of7 wkofhemodialysis.

The results obtained from Group III patients are

shown in Fig. 4. Each of these seven, stable chronic

100

95. 90* E 85

1

E

W 80

75, 70*

100-

95-90 85- 80-

75-70- P<0.001

78.5±2.1 878±1.3

BEFORE AFTER BEFORE

DIALYSIS DIALYSIS DIALYSIS DIALYSISAFTER

FIGupRE3 ComparisonoftheskeletalmuscleEmbeforeand

after 7 wk ofhemodialysis. On the left are individual Em

measurements,andonthe rightarethemean(+SEM)values. 110

100

90

80

E

E

wi

70

60-ELECTRODE PATIENT NUMBER

(5)

100

;

90-E

E w

80-70* ±91.21.0 3

80.1

±0.8

2

DIALYSIS PER WEEK

FIGURE 4 Theeffect of reduced dialysisontheEmof

skele-tal muscle. Individual Em measurements obtained on 6-h, thrice-weekly hemodialysis are shown on the left. On the right are the Em values after6 wk of reduced dialysis (6h orless,twice weekly).

hemodialysis patients had a normal Em on thrice-weekly dialysis. After 6 wk of reduced dialysis to 6 h twice weekly, the Em fell in three patients.

Addi-tionalreductions intime on dialysis were required in

the other fourpatients. Onepatientrequireda reduc-tion to 4.5 h twiceweekly, anotherto4h twiceweekly, anotherto 3 h twiceweekly, and the lastpatientto 2.5 h twice weekly. At thetime the Em became abnormal,

onepatientcomplained of early morning nausea,and

two complained of general malaise. The others

re-mained asymptomatic. Table III illustrates data on

body surface area, residual Ccr, and dialysistime per

week required toreduce theEm. Minimal dialysis

re-quirements to sustain anormal Em bore no apparent

relationshiptoeither residual renalfunctionorthebody surface area.

TableIVdepicts laboratorymeasurementsobtained

on thrice-weekly dialysis and again on twice-weekly dialysis. Those values shownontwice-weeklydialysis

were taken from weeklymeasurements obtained

dur-TABLEIII

Body SurfaceAreaandCcrinPatientsonReduced Dialysis

Patient Body surfacearea cer Dialysistime*

m2 cm3/min hlwk

1 1.70 2.4 12 2 2.08 2.3 12 3 2.0 0.3 12 4 2.04 2.2 9 5 1.84 <0.25 8 6 2.0 1.15 6 7 1.70 <0.25 5

*Time ondialysis atwhich Em returned to low value.

ingthe 6 wk before developing an abnormal Em. Sig-nificant changes were noted in the serum creatinine andhematocrit. No significant change was noted in the blood urea nitrogen, albumin, or potassium.

Fig. 5 demonstrates serial Em measurements in a single patient when dialysis time was varied from thrice to twice weekly on more than one occasion. This man was 53 yrold, was actively working more than 40 h/wk in a service station, and stated that he felt well. He had been maintained on twice-weekly dialysis, 6 h/ treatmentfor3yr. His Em measurement onthis twice-weekly regimen was -78 mV.Whendialysis time was increased to 6 h thrice weekly, his Em measurements initiallybecameabnormally high and returned to

nor-malat4wk. When dialysis time wasdecreasedto 6 h twice weekly, the membranepotentialreturned to ab-normally low values. It once againreturnedtonormal

after increasing dialysis time to 6 hthrice weekly. Of

interest,thepatientsubsequently revealedthatfor the3

yr while he was on the twice-weekly hemodialysis regimen,he had experienced early morning nausea. On

thrice-weeklydialysis this symptom was resolved, and

his general well-being improved.

DISCUSSION

Among the major factors that maintain the electrical potential differenceacrosstheplasma membrane ofthe

striated muscle cell are the electrical activity of

im-permeable intracellular polyanions, differential ionic

permeability

ofthe membrane, and sodium transport.

Accordingly, several abnormalities could be

respon-sible for the depressed Em in uremia. One could

be a deficit of high molecular weight intracellular

polyanions that normally maintain an electrical

dif-fusion potential forK+. Thus an impermeableanion, such as a protein, could become deficient in concen-tration,undergo a change in its isoelectric point, orits

charges or could become partially neutralized by an

uremic toxin. None of these possibilities has been examined.

Asecond factorresponsible for the lowEm in uremia

could be an increased sarcolemma permeability to

sodium ions. If the cellular permeability to Na ions were increased, and all other factors remained the same, one could predict from the Goldman equation2 (2) that theEm would fall. For example, if the normal

permeabilityratio (p) ofNa to K is 0.01, thepredicted

Em is -87 mV. An increaseof p to0.08would resultin an Emof-60 mV. However,to maintainintracellular

concentrations of sodium in the normal range, the

2Em =-61.5 log

[K]i/([K]0

+

p[Na]0).

For this application,

assumeelectrolyteconcentrationsinside(i)andoutside(o)the cell remain unchanged; i.e., [K]i= 155 meq/liter; [K]°= 4.5

meq/liter; [Na]0= 145meq/liter.Thevalue for pis normally

0.01.

(6)

TABLE IV

Laboratory Measurements

Bloodurea nitrogen Creatinine Hematocrit Albumin K+

mgilOOml mgilOOml vol% gIlOOml meqiliter

Thrice-weeklydialysis 88+7.8* 20+2.5 25+2.8 4.3+0.1 4.7+0.3

Twice-weekly dialysist 98±9.8 24±2.5 22±2.9 4.2±0.1 4.8±0.3

P NS <0.01 <0.05 NS NS

*Mean±SEM.

tLaboratoryvalues ontwice-weekly dialysisare thosemeasuredduringthe 6 wk before

developingalowmembranepotential.

sodium pump mustbe capable of responding to this leak in a mannersuch that sodiumions areextrudedas rapidly as they enterthe cell. Therefore,to accountfor

ourfindings,onecouldpropose that either the pump

ac-tivityitselfmustbedepressed,oritscapacityhasbeen exceeded.

Bolteetal. havealso reported abnormally lowresting

membrane potentials in patients with uremia (5). In

addition, they examined the effects of acute uremia onelectrical properties of fibersfrom skeletal muscle and frompapillary muscles ofguinea pighearts (6).

De-creased effective membrane resistance, reflecting

in-creased conductance, and prolonged duration ofaction

potentialswereconsideredto infer increased

permea-bilityas a resultofprimary plasma membrane injury. To ourknowledge,nodirectstudiesof cellular

permea-bility have been conducted in either uremic man or

animals.

In contrast to thepaucity of information on cellular

0 1 2 3 4 0 1 2 3 4 5 6 0 1 2 3

5YEARS

TIME IN WEEKS

FIGuRE5 Serial skeletal muscle Em measurements in a

singlepatient. The Em becameabnormallylow on each oc-casion when dialysis was reduced to 6h twice weekly (12

h/wk), and returned to normal when dialysis time was in-creased to6hthrice weekly (18 h/wk).

permeability,numerous investigators have found

evi-dence that active sodium transport is impaired in uremia. The classic study by Welt et al. (3) demon-strated impairedactivityof the ouabain-sensitive,

Mg-dependent, Na-K-activated ATPase, and elevated Na contentof erythrocytes frompatients withuremia.

These findingshave been amply confirmed by others (7, 8). Unfortunately, such abnormalitiesarenotfound

in allpatients. Welt et al. found highNa content and depressedATPaseactivityof erythrocytesin25%of the

patients. Of interest, both defects were more

pro-nounced in thosemost seriously ill. In contrast to the

inconsistent abnormalities in uremic erythrocytes, our

observations indicate that the Em bears a linear

rela-tionshiptoendogenous Ccr once thelatter falls below

6.3 cm3/min. Based upon our present and previous

studies of seriouslyill patients withuremia(1, 2),an ab-normally lowEmhasgenerally been associated withan

elevatedcellularconcentrationofNa(Fig. 6). Forthis

reason, webelieve thata depressedEm reflects func-tional cellular injury. These consistent findings

indi-catethat skeletal muscle ismoreuniformly affected in

uremia than erythrocytes. Although our observations havenotidentified thespecific defect responsible, the

evidence would appear to favor either an increase of permeabilityor suppressedNa transport, orboth.

These studies showforthe first time that treatmentby

hemodialysis can restore both Em and cellular com-position tonormal. Indeed, serial observations onone case (Fig. 5) whose Em became hyperpolarized after increaseddialysis,would be consistent with the notion thatthecapacityof suchanelectrogenictransport

proc-ess may actually be increased, or perhaps even be adaptedinchronic renal failure.Itseemspossible that suchanadaptation couldoccurinresponse tosustained

hyperpermeability

ofthe musclecelltosodium ions. Even

(7)

50-

45-

40-

~32-0

- 30'

cr25

E 20 Z 15 10 5.

A A\

A A

0

AAl

0

AO\A

0

A A@

\AA

0

A0

A0

60 65 70 75 80 85 90

Em (-mV)

95 100

FIGURE6 Comparison of skeletal muscle intracellular

sodiumconcentration[Na]' andEmmeasurements in patients with chronic renal failure. Measurements made

previ-ouslyinourlaboratoryaredepicted by (A) from Cunningham

etal. (1) and by(0) from Bilbrey et al. (2). Measurements

from this report are shown by the symbol (0). A significant

relationship exists betweenareduced Emandanincreased

[Na]' in skeletal muscle (r=0.74; Em=89.7-0.6 [Na]';

P<0.001). ICW, intracellularwater.

would be unleashed and hyperpolarization could oc-cur. Hypothetically, such a situation could occur

un-der conditionsof increased pump capacity, acontinued sodium leakto sustainhyperactivity ofasodiumpump, and a lack of suppressive toxins. Withcontinued

dialy-sis therapy, permeability ofthe cell to sodium would be restored to normal. The latter situation would be

consistent with ourfindings of normal electrochemical

characteristics of the cells after 7 wk of adequate dialysis therapy.

We assume that restoration of the electrochemical

characteristics of muscle cells to normal by dialysis represents anideal goal of therapy. Thus it seems pos-sible that serial observationsonmuscleEmmay

consti-tute apotentially powerful tool to assess adequacy of dialysis therapy. Further studiesare necessary to evalu-ate this possibility.

ACKNOWLEDGMENTS

The authorsexpresstheirgratitude toDonnaTalmon,James Long, Cora Elliott, Julio Borroto, and Patsy Robinson for theircontributionsto this work.

This studywas supportedby theVeterans Administration Intramural Research Supportfund and U. S. Public Health

Service grantSPOlHE11662.

REFERENCES

1. Cunningham, J. N., N. W. Carter, F. C. Rector, Jr., and

D. W.Seldin. 1971.Restingtransmembrane potential dif-ference of skeletal muscleinnormalsubjects andseverely

ill patients. J.Clin. Invest. 50: 49.(Abstr.)

2. Bilbrey,G.L., N. W.Carter, M. G.White,J. F.Schilling, andJ. P.Knochel.1973. Potassium deficiencyinchronic renalfailure. KidneyInt. 4: 423.(Abstr.)

3. Welt,L.G.,E.K. M.Smith, M.J. Dunn, A.Czerwinski,

H.Proctor, C.Cole,J. W.Balfe, andH.J.Gitelman.1967.

Membranetransport defect: The sick cell.Trans. Assoc. Am.Physicians(Philadelphia). 80: 217. (Abstr.)

4. Patrick,J.,andN. F.Jones. 1974.Cell sodium,potassium

andwater in uremiaandthe effects of regular dialysisas

studied in the leucocyte, Clin. Sci. Mol. Med. 46: 583.

(Abstr.)

5. Bolte,H. D., G.Riecker, andD. Rohl. 1963.Messungen

des Membranpotentials and einzelnen guergestreiften

Muskelzellen des Menschen in situ.Klin. Wochenschr.

41: 8. (Abstr.)

6. Bolte, H. D., E. Becker, andW. Volker. 1972. Changes ofionicpermeability ofskeletaland heart muscle cellu-larmembranesinrenal insufficiency.In Uremia: An

Inter-national Conference on Pathogenesis, Diagnosis and

Therapy. R. Kluthe, G. Berlyn, andB. Burton, editors. Georg ThiemeVerlagKG., Stuttgart. 14-18.

7. Cole,C.H.1973.Decreased ouabain-sensitive adenosine triphosphatase activity in the erythrocyte membrane of

patients withchronic renal disease. Clin.Sci.Mol. Med.

45: 775.(Abstr.)

8. Kramer, H. J., D.Gospodinov, andF.Kruck. 1976.

Func-tional and metabolic studies on red blood cell sodium

transport inchronicuremia.Nephron. 16: 344.(Abstr.)

506 J.R. Cotton, T. Woodard, N. W. Carter, andJ.P. Knochel v-r

References

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