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
werestnidied
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-weeklyThis 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
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.
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 chlorideconcentration;
[K]',
intracellularpotassium 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
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.
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
50-
45-
40-
~32-0
- 30'
cr25
E 20 Z 15 10 5.
A A\
A A
0
AAl
0
AO\A
0A 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.
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