ema
Swit
See Editorial, pages 805–806
a r t i c l e i n f o
Article history:
Accepted 8 January 2010
Available online 23 February 2010
ll rights
eserved.
In general, routine electromyography and muscle enzymes are resistance, carnitine deficiency and malnutrition especially with
protein deficiency (Fahal et al., 1997; Kunis et al., 2001; Campistol,
2002; Al-Hayk and Bertorini, 2007). Other hypotheses include
anemia, alterations in mitochondrial metabolism and abnormal
oxygen conductance from the microcirculation to mitochondria,
possibly due to reduced capillary/fiber ratio andwidening of the cap-
illary basement membrane (Campistol, 2002). Finally, water and
electrolyte disturbances such as hyperkalemia and acidosis could
very well account for the functional abnormalities and would typi-
cally result in no structural correlates (Brouns and De Deyn, 2004).
Abbreviations: ISI, inter-spike interval; NC, normal control; RRP, relative
refractory period; ESN, early supernormality (peak percentage increase in velocity
at intervals up to 15 ms after a conditioning impulse); SN100, supernormality at
100 ms (percentage increase in velocity); VRC, velocity recovery cycle; XSN100,
extra supernormality at 100 ms due to a second conditioning impulse.
* Corresponding author. Address: Sobell Department, Institute of Neurology,
Queen Square, London WC1N 3BG. Tel.: +44 (0) 20 7937 3611; fax: +44 (0) 20 7813
3107.
Clinical Neurophysiology 121 (2010) 874–881
Contents lists availab
Clinical Neuro
journal homepage: www.elE-mail address: H.Bostock@ion.ucl.ac.uk (H. Bostock).1. Introduction
‘Uremic myopathy’ is a term used for a common deficiency in
muscle function in patients with end-stage renal disease (Serratrice
et al., 1967; Floyd et al., 1974) with an overall prevalence of approx-
imately 50% (Clyne, 1996). Clinical signs include limb weakness,
muscle wasting, fatigue, limited endurance, and exercise limitation.
within normal limits (Campistol, 2002). Muscle biopsies only occa-
sionally reveal structural alterations such as muscle fiber atrophy
(Diesel et al., 1993). This indicates that functional abnormalities
primarily cause the clinical signs described above. Several, often
interrelated pathogenetic mechanisms have been identified: de-
creased clearance of uremic toxins, abnormalities in Vitamin D
metabolism including secondary hyperparathyroidism, insulin 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. A
rhyperkalemia may therefoSignificance: Chronic muscle membrane depolarization by hyperkalemia may account for some of the
functional deficits in uremic myopathy. Consistent normalization of membrane potential by avoiding
re reduce symptoms of ‘uremic myopathy’.Keywords:
Muscle membrane potential
Muscle velocity recovery cycle
Relative refractory period
Supernormality
Haemodialysis
Uremic myopathy1388-2457/$36.00  2010 International Federation o
doi:10.1016/j.clinph.2010.01.024a b s t r a c t
Objective: To test the hypothesis that muscle fibers are depolarized in patients with chronic renal failure,
by measuring velocity recovery cycles of muscle action potentials as indicators of muscle membrane
potential.
Methods: Velocity recovery cycles were recorded from brachioradialis muscle by direct muscle stimula-
tion in 13 patients, before, immediately after, and 1 h after haemodialysis, and compared with those from
10 age-matched controls.
Results: In the patients, supernormality was reduced by 47%, and relative refractory period increased by
60.5% compared with controls (both P < 0.001). Dialysis normalized the supernormality, but an hour later
it was again reduced. These changes in supernormality were strongly correlated with the changes in
serum potassium levels (P < 0.0001). A late component of supernormality, attributed to potassium accu-
mulation in the t-tubule system, was also reduced in the patients but remained abnormally low after
dialysis.
Conclusions: Muscle membranes in the patients were chronically depolarized by hyperkalemia. Whereas
dialysis transiently normalized muscle membrane potential, it was not adequate to normalize t-tubule
function.bDepartment of Neurosurgery, Inselspital, Bern University Hospital and University of Bern, Switzerland
cDepartment of Nephrology and Hypertension, Inselspital, Bern University Hospital and University of Bern, Switzerland
d Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UKVelocity recovery cycles of human muscl
W.J. Z’Graggen a,b, F. Aregger c, S. Farese c, A.M. Hum
aDepartment of Neurology, Inselspital, Bern University Hospital and University of Bern,f Clinical Neurophysiology. Publishaction potentials in chronic renal failure
, C. Baumann a, D.E. Uehlinger c, H. Bostock d,*
zerland
le at ScienceDirect
physiology
sevier .com/locate /c l inphed by Elsevier Ireland Ltd. All rights reserved.

There is evidence that axons are depolarized in many patients
with chronic renal failure, and that this depolarization is fully
accounted for by hyperkalemia (Krishnan et al., 2005). It has also
been shown that haemodialysis produces rapid and significant
normalization of nerve membrane potential (Kiernan et al.,
2002).
In nerve excitability testing, the recovery cycle after a single
supramaximal stimulus has been found to provide information
about axonal membrane potential and ion channel function in
neuropathies. Recently, we have adapted this method to human
muscle fibers, by measuring the changes in conduction velocity
of muscle fibers following one or two conditioning impulses, using
direct muscle stimulation and recording via needle electrodes
(Z’Graggen and Bostock, 2009). Measuring muscle fiber velocity
recovery cycles (VRC) is therefore a highly appropriate tool for
investigating uremic myopathy, in which membrane depolariza-
tion is a likely etiological factor.
The present study was undertaken to test the hypothesis that
muscle fibers are depolarized in uremic patients, and to study
the effect of haemodialysis on muscle membrane potential. Also,
various serum parameters associated with uremic myopathy were
determined to gain insight into mechanisms affecting muscle fiber
membrane potential.
53.9 years; eight males, one female) recordings were repeated
immediately after and again about 1 h (mean 54.8 m) after termina-
tion of dialysis treatment. Recordings were compared to recordings
on 10 age-similar, normal control subjects (NCs) (aged 37–73 years;
mean 52.3 years; three males, seven females). All procedures were
approved by the local ethics committee (Kantonale Ethikkommis-
sion Bern, Switzerland) and conformed to the Declaration of Hel-
sinki. Subjects and patients gave written informed consent to
participate in the study.
2.2. Stimulation
Subjects/patients were comfortably seated in a warm room,
with the angle of the elbow set close to 90, and blankets applied
if necessary so that arm surface temperature was in the range
31.5–33 C. Studies were performed using a recently described
protocol (Z’Graggen and Bostock, 2009). In brief, as cathode an
insulated monopolar needle electrode was used (TECA, VIASYS
Healthcare, Madison, Wisconsin, USA). The electrode was inserted
perpendicularly into the brachioradialis muscle at about 25% of the
distance from the lateral epicondyle of the humerus to the styloid
process of the radius. Brachioradialis was selected as it has a rela-
tively well-defined end-plate zone, to avoid stimulation of the
motor axons (Mihelin et al., 1991; Z’Graggen and Bostock, 2009).
PTH
(ng
373
178
115
66
284
165
242
229
190
602
363
189
27
f ha
ith
W.J. Z’Graggen et al. / Clinical Neurophysiology 121 (2010) 874–881 875Table 1
Clinical characteristics of patients with chronic renal failure.
Patient Sex Age
(years)
Renal diagnosis Co-morbi-
ditiesa
Diabetes
Y/N
1 F 35 Focal segmental
glomerulosclerosis
4 N
2 M 51 Diabetic nephropathy 5 Y
3 M 51 Refluxnephropathy 3 N
4 M 55 Glomerulonephritis 4 N
5 M 55 Diabetic nephropathy 4 Y
6 M 57 Glomerulonephritis 5 N
7 M 59 HBV infection associated
Glomerulonephritis
5 N
8 M 64 Diabetic nephropathy 5 Y
9 M 65 IgA Nephropathy 5 N
10 M 52 Glomerulonephritis 5 N
11 F 69 Membranous
glomerulonephritis
6 N
12 F 83 Autosomal dominant
polycystic kidney disease
3 N
13 M 87 Nephroangiosclerosis 5 N
N.B. Patients 1–9 were studied before, immediately after, and ca. 1 h after the end o
a Charlson comorbidity index.
b Parathyroid hormone levels (normal limits: 150–300 ng/l), PTH was measured w2. Methods
2.1. Subjects and ethical approval
Recordings were made immediately before haemodialysis treat-
ment in 13 patients (10 males, 3 females; aged 35–87 years (mean
59.8 years)) undergoing chronic haemodialysis treatment at the
University Hospital Bern. All patients were treated by a conven-
tional 3 weekly dialysis regimen with high-flux polysulfone
membranes. Online postdilution hemodiafiltration was applied in
four out of 13 patients. Dialysis was delivered through an AV fistula
or an AV graft in 10 patients, whereas three patients were treated
with catheters as a temporary dialysis access (for clinical character-
istics see Table 1). In nine patients (aged 35–65 years; meanc 1 = high flux; 2 = postdilution hemodiafiltration.
d Equilibrated Kt/V.
e Normalized protein catabolic rate.A non-polarizable surface electrode was used as anode (Red Dot,
3 M Health Care, D-46325 Borken, Germany). The anode was taped
on the skin at about 1 cm distal to the cathode. Stimulus wave-
forms (rectangular current pulses of 0.05 ms duration) generated
by a computer were converted to current with an isolated linear
bipolar constant-current stimulator (DS5, Digitimer Ltd., Welwyn
Garden City, Hertfordshire, UK).
2.3. Recording
For recording a concentric 30G EMG electrode (Medtronic,
Skovlunde, Denmark) was used. This electrode was inserted into
the brachioradialis muscle about 15–25 mm proximal to the cath-
ode. Small position changes were made until a stable monophasic
response could be recorded with stimulus amplitudes of less than
10 mA. The signal was amplified (gain 1000, bandwidth 1.6–2 kHz)
b
/l)
Residual
clearance
(ml/min)
Residual urine
output
(ml/24 h)
Dialyis
modalityc
Dialysis
vintage
(months)
eKt/Vd nPCRe
(g/kg/d)
0 0 1 176 1.82 1.36
3.9 880 1 16 1.47 1.09
0 0 1 276 1.47 0.76
0 0 1, 2 125 1.65 1.03
0 0 1 18 0.92 0.93
0 150 1, 2 18 1.4 1.07
2 1000 1 5 1.25 1.12
6.5 2045 1 27 1.41 1.39
1 500 1 24 1.13 0.83
1.7 300 1, 2 28 1.3 1.1
0 0 1, 2 41 1.6 0.41
2.6 1300 1 16 1.42 1.06
3 1020 1 3 0.94 1.31
emodialysis. Patients 10–13 were studied only before haemodialysis.
in in an interval of 3–4 weeks.