Altered motor nerve excitability in end-stage kidney disease

doi:10.1093/brain/awh558 Brain (2005) of 11

Altered motor nerve excitability in end-stagekidney disease

Arun V. Krishnan,1,2 Richard K. S. Phoon,3 Bruce A. Pussell,3 John A. Charlesworth,3

Hugh Bostock4 and Matthew C. Kiernan1,2

1Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, Sydney, Australia, 2Prince of Wales MedicalResearch Institute and Prince of Wales Clinical School, University of New South Wales, 3Department of Nephrology,Prince of Wales Hospital, Randwick, Sydney, Australia and 4Sobell Department of Neurophysiology, Institute of Neurology,Queen Square, London, UK

Correspondence to: Dr Matthew Kiernan, Prince of Wales Medical Research Institute, Barker Street, Randwick,Sydney, NSW 2031, AustraliaE-mail: [email protected]

Although multiple toxins have been implicated in the development of uraemic neuropathy, no causative agenthas been identified. In the present study, the excitability properties of lower limb motor nerves in patients withend-stage kidney disease treated with haemodialysis were measured before, during and after a standard 5 hhaemodialysis session, in an attempt to explore the pathophysiology of uraemic neuropathy. Compound muscleaction potentials were recorded from tibialis anterior and extensor digitorum brevis, following stimulationof the common peroneal nerve in 14 patients. Measures of excitability were assessed in relation to changesin serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, parathyroid hormoneand b-2-microglobulin. Before dialysis, measures of nerve excitability were significantly abnormal in thepatient group for axons innervating tibialis anterior and extensor digitorum brevis, consistent with axonaldepolarization: refractoriness was increased and superexcitability and depolarizing threshold electrotonuswere reduced. Pre-dialysis excitability abnormalities were strongly correlated with serum K+. Correlationwas also noted between the severity of symptoms and excitability abnormalities. Haemodialysis normalizedthe majority of nerve excitability parameters. In conclusion, lower limb motor axons in uraemic patientsare depolarized before dialysis. The correlation between serum K+ and excitability measures indicates thathyperkalaemia is primarily responsible for uraemic depolarization, and a likely contributing factor to thedevelopment of neuropathy.

Keywords: membrane potential; nerve excitability; potassium; threshold electrotonus; uraemic neuropathy

Abbreviations: b-2M = b-2-microglobulin; CMAP = compound muscle action potential; EDB = extensor digitorum brevis;ESKD = end-stage kidney disease; NCS = nerve conduction study; NSS = neuropathy symptom score; PTH = parathyroidhormone; SNAP = sensory nerve action potential; TA = tibialis anterior; TEd = depolarizing threshold electrotonus;TEh = hyperpolarizing threshold electrotonus; T-NSS = total neuropathy symptom score

Received February 24, 2005. Revised April 10, 2005. Accepted May 12, 2005

IntroductionPeripheral neuropathy in end-stage kidney disease (ESKD)

presents as a length-dependent, distal sensorimotor poly-

neuropathy with greater lower limb than upper limb

involvement (Bolton, 1980; Asbury, 1993). Previous studies

of neuropathy in ESKD have demonstrated prevalence rates

which vary from 60 to 100%, depending on the choice of

nerve segments, the indices measured and the number of

nerves studied (Nielsen, 1973; Bolton, 1980; Ackil et al.,

1981; Van den Neucker et al., 1998; Laaksonen et al., 2002).

The pathophysiology of uraemic neuropathy has not been

established. The finding that neurological complications of

renal failure may be improved by dialysis (Hegstrom et al.,

1962) and that patients receiving peritoneal dialysis had a

lower incidence of neuropathy than haemodialysis patients

gave rise to the ‘middle molecule hypothesis’ (Babb et al.,

1971). This hypothesis postulated that the higher rate of

neuropathy in patients on haemodialysis was secondary to

retention of toxic molecules in the middle molecular range

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of 300–12 000 Da (Vanholder et al., 1994), given that these

substances were poorly cleared by haemodialysis membranes.

Examples of such molecules include parathyroid hormone

(PTH) and b-2-microglobulin (b-2M), the levels of which

are elevated in patients with ESKD (Vanholder et al., 1994).

The hypothesis, however, remains unproven and the toxicity

of a number of these middle molecules remains contentious

(Vanholder et al., 1994; Bostock et al., 2004).

Measurements of nerve excitability, which provide infor-

mation about membrane potential and biophysical properties

of peripheral axons (Bostock et al., 1998; Burke et al., 2001),

have been used to study peripheral nerves in patients with

neuropathy and have provided information about disease

pathophysiology (Cappelen-Smith et al., 2001; Kiernan et al.,

2001a, 2002a, 2005; Kanai et al., 2003; Nodera et al., 2004).

A preliminary study of motor nerve excitability in the upper

limb of patients with ESKD demonstrated membrane poten-

tial changes—specifically membrane depolarization before

haemodialysis (Kiernan et al., 2002b)—with subsequent

improvement in nerve excitability after dialysis. Given the

length-dependent predisposition of uraemic neuropathy, typ-

ically worse in the legs than in the arms, the present study

has focused on lower limb motor nerve excitability. The aim

of the study was to expand the original study by investigating

the excitability properties of lower limb motor axons, before,

during and after haemodialysis in patients with ESKD.

In addition, correlations were explored between excitability

changes and the clinical severity of neuropathy, related to

changes in the serum levels of potential uraemic toxins and

the severity of neuropathic symptoms.

MethodsStudies were undertaken on 14 patients with ESKD (8 men, 6 women:

age range, 17–69 years; mean age, 50.3 years) receiving thrice-weekly

haemodialysis, using a biocompatible low-flux polysulfone mem-

brane (Fresenius, Bad Homburg, Germany). All patients were

dialysed against a K+ concentration of 2 mmol/l. None of the

patients had a history of other illnesses known to cause neuropathy

such as diabetes or amyloidosis and there was no history of exposure

to neurotoxic medications, including immunosuppressive therapy.

The causes of ESKD in this group were glomerulonephritis

(9 patients), polycystic kidney disease (1), medullary cystic kidney

disease (2) and hypertensive vascular disease (2).

Patients gave informed consent to the procedures, which were

approved by the South East Sydney Area Health Service Human

Research Ethics Committee (Eastern Section) and the Committee

on Experimental Procedures Involving Human Subjects of the Uni-

versity of New South Wales. The studies were performed in accord-

ance with the Declaration of Helsinki.

A neurological history and examination were initially undertaken

and symptoms were graded using the neuropathy symptom score

(NSS) (Dyck et al., 1980, 1987, 1992; Laaksonen et al., 2002). Patients

were asked about the presence of motor symptoms in the limbs

(subset IB) and sensory symptoms, both negative (subset IIA) and

positive (subset IIB). Each symptom received a score of 1 and the

number of symptoms present in each subset was added to give a

total neuropathy symptom score (T-NSS). The maximum possible

T-NSS was 9.

Routine nerve conduction studies were undertaken in all patients.

Neurophysiological indices which had previously been shown to be

sensitive markers of uraemic neuropathy were evaluated (Ackil et al.,

1981; Laaksonen et al., 2002). Studies were undertaken on the sural,

tibial, common peroneal and superficial radial nerves using a Mede-

lec Synergy system (Oxford Instruments, Surrey, UK) and conven-

tional nerve conduction techniques (Burke et al., 1974; Kimura,

1983). Nerve stimulation was performed at a frequency of 1 Hz

for motor nerves and 2 Hz for sensory nerves. Motor amplitudes

were measured peak to peak and sensory amplitudes were measured

as an average of the rising and falling phase amplitudes. Latency was

measured to the onset of the compound potential. For sensory stud-

ies, a bipolar recording electrode configuration was used with a

standard interelectrode distance of 4 cm (Eduardo and Burke,

1988). For tibial nerve F-wave studies, the latency was recorded as

the mean of 10 responses following supramaximal stimulation of the

nerve at the medial malleolus.

The excitability properties of lower limb motor nerves in patients

with ESKD treated with haemodialysis were measured before, during

and 1 h after a standard 5 h haemodialysis session using a previously

described protocol (Kiernan et al., 2000; Krishnan et al., 2004).

Recordings were obtained from tibialis anterior (TA) and extensor

digitorum brevis (EDB), following stimulation of the peroneal nerve

at the fibular neck. Skin temperature was monitored close to the site

of stimulation for the duration of each study.

Serum electrolytes, urea, creatinine, PTH and b-2M

were measured at the time of the excitability studies. Kt/V, a standard

and commonly accepted measure of dialysis adequacy (Daugirdas,

1995, 2000), was also calculated according to the following formula,

where K is the dialyser clearance, t is the length of the dialysis session

(hours) and V is the urea distribution volume (litres), U1 is pre-

dialysis urea (mmol/l); U2 is post-dialysis urea (mmol/l, 1 h after

dialysis), BW is body weight, DBW is the change in body weight

following dialysis.

Kt=V ¼ �ln U1=U2 � 0:008 · tð Þ þ 4 � 3:5 · U1=U2ð Þ · DBW=BW: ð1Þ

The current required to produce the desired CMAP (compound

muscle action potential) amplitude was determined using a compu-

terized threshold-tracking program (QTRAC version 5.2a, Institute

of Neurology, Queen Square, London, UK, with multiple excitability

protocol TRONDXM2) that was run on a Pentium computer

(Kiernan et al., 2000). Recordings were amplified (gain 1000,

bandwidth 5–10 kHz) and digitized using an analogue-to-digital

(A/D) board (DT2812, Data Translation, Marlboro, MA, USA),

with a sampling rate of 10 kHz. Stimulus waveforms were converted

to current using a purpose-built isolated linear bipolar constant-

current stimulator.

Stimulus–response curves were generated for test stimuli of 0.2

and 1 ms duration (Fig. 1). The slope of the 1 ms stimulus–response

curve and the magnitude of the tracking ‘error’ (i.e. the difference

between measured response and target response) were used to

optimize the subsequent threshold tracking. The peak 1 ms response

was also used to calculate the target response (40% of the supra-

maximal CMAP response). The ratio between the stimulus–response

curves for the two different stimulus durations was used to calculate

rheobase (Burke et al., 2001) and the strength–duration time con-

stant (tSD) of motor axons of different thresholds using Weiss’s

formula (Weiss, 1901; Mogyoros et al., 1996).

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The threshold changes that occur in response to subthreshold

depolarizing and hyperpolarizing pulses, referred to as threshold

electrotonus, were measured by altering nerve excitability using sub-

threshold polarizing currents of 100 ms duration, set to 40% of the

unconditioned threshold current (Bostock and Baker, 1988; Kiernan

et al., 2000; Burke et al., 2001). A current–threshold relationship,

analogous to the conventional current–voltage (I/V) relationship

(Kiernan et al., 2000), was obtained by tracking the changes in

threshold of 1 ms test pulses that occurred following subthreshold

polarizing currents of 200 ms duration. In the final part of the

Fig. 1 Six plots of excitability parameters recorded from TA for a single representative patient (continuous lines with circles) before dialysiswith 95% confidence intervals (broken lines) for a single subject (Krishnan et al., 2004). (A) Absolute stimulus–response relationship forstimuli of 0.2 ms duration (line without filled circle) and 1 ms duration (line with filled circle). The filled circle on the 1 ms response curvecorresponds to the threshold for a CMAP 50% of maximum and the broken ellipse corresponds to the 95% confidence limits for a singlesubject. (B) Normalized stimulus–response relationship. The responses in (A) are expressed as a percentage of maximum and the stimuli asa percentage of the stimulus for a response 50% of maximum. (C) Current–threshold relationship, reflecting rectifying properties of theaxon following polarizing currents, expressed as a percentage of resting threshold. Threshold changes to hyperpolarizing current arerepresented on the left and to depolarizing current on the right. (D) Distribution of strength–duration time constants of nine populations ofaxons, from 5 to 95% of maximal CMAP in groups of 10%. (E) Threshold electrotonus. Threshold changes to polarizing currents of 640%of the resting threshold. Changes are plotted as threshold reductions, with depolarization represented in an upward direction andhyperpolarization in a downward direction. (F) Recovery cycle, showing refractoriness superexcitability and late subexcitability.See text for further details.

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protocol, the recovery cycle of excitability of motor axons was

assessed by tracking the changes in threshold that occurred following

a supramaximal conditioning stimulus of 1 ms duration.

Abnormalities of nerve conduction and excitability were estab-

lished by comparing the results with normative data from our unit

(Burke et al., 1974; Krishnan et al., 2004) and other centres (Ma et al.,

1981; Ma and Liveson, 1983; Buschbacher, 1999; Puksa et al., 2003).

Excitability results were corrected for age, temperature and gender

(Kiernan et al., 2001b). Single comparisons in excitability parameters

were analysed using Student’s unpaired t-test for comparisons with

normative data (n = 25; age range, 22–60 years; mean age, 31 years)

and Student’s paired t-test for comparisons before and after dialysis.

Logarithmic conversions were undertaken to normalize certain

variables. Correlations were analysed using Pearson’s correla-

tion coefficient. A probability value of <0.05 was considered statist-

ically significant. Results are expressed as mean 6 standard error of

the mean.

ResultsNerve conduction studies andneuropathy assessmentThe amplitude of sural nerve SNAP (sensory nerve action

potential) (Burke et al., 1974) was reduced in 71% of patients

(Table 1) and in the entire group as a whole (mean sural SNAP

amplitude, 5.8 6 1.1 mV; n = 14), with a minor reduction in

sural nerve conduction velocity (Table 1). Superficial radial

SNAP amplitude (Ma et al., 1981) was reduced in 50% of

patients (mean, 18.1 6 2.4 mV), although conduction velocity

was generally preserved (mean, 53.6 6 0.9 m/s).

Abnormalities of lower limb motor conduction were

also demonstrated in a number of patients with neuro-

pathy (Table 1). Tibial CMAP amplitudes (Buschbacher, 1999)

were reduced in 43% of patients and mean tibial CMAP

amplitude was mildly reduced (mean tibial CMAP amplitude,

3.6 6 0.7 mV). Tibial distal motor latency was prolonged in

38% of patients although mean latency was within the normal

range (mean tibial distal motor latency, 5.2 6 0.5 mV). Tibial

F-wave minimum latency (Puksa et al., 2003) was prolonged

in 43% of patients (Table 1) and persistence was reduced

in 43% of patients. Peroneal CMAP amplitudes (Ma and

Liveson, 1983) were reduced in 21% of patients and

there was a mild reduction in mean CMAP amplitude

(mean peroneal CMAP amplitude, 3.2 6 0.5 mV). These

changes were accompanied by a reduction in peroneal

nerve conduction velocity in 36% of patients, although the

mean value was within the normal range (mean peroneal

nerve conduction velocity, 43.4 6 1.6 m/s). Peroneal distal

motor latency was normal in all patients in whom a CMAP

response was evident.

All ESKD patients in the study reported symptoms of

neuropathy (Table 2), with an average of approximately

two symptoms per patient (mean NSS 1.9 6 0.2). The severity

of neuropathy in the present study (Table 2) was staged

as follows using a modified form of a previously devised

system (Dyck, 1988): Stage 0, no neuropathy [T-NSS < 2

with normal NCS (nerve conduction study)]; Stage 1, asymp-

tomatic neuropathy (T-NSS = 0 with abnormalities on NCS);

Stage 2, symptomatic neuropathy (T-NSS > 2 with normal

NCS or T-NSS � 1 with abnormal NCS; neuropathic symp-

toms non-disabling); Stage 3, disabling neuropathy (T-NSS �2 with normal NCS or T-NSS � 1 with abnormal NCS;

neuropathic symptoms reported to be disabling). Using

this scale, 1 patient had no neuropathy (stage 0), 10 had

Stage 2 neuropathy and 3 had Stage 3 neuropathy (Table 2).

Table 1 Nerve conduction parameters for each patient

Patient SuralSNAP (mV)

RadialSNAP (mV)

TibialCMAP (mV)

TibialDML (ms)

Tibial F-wave min.latency (ms)

Tibial F-wavepersistence (%)

PeronealCMAP (mV)

PeronealDML (ms)

1 6.0* 15.0* 4.4 7.7* 51.9 100 4.7 3.52 2.0* 11.0* 2.8* 6.9* 59.8* 90 2.1 3.43 3.1* 9.0* 1.8* 4.2 44.6 60* 2.5 3.54 1.5* 13.0* 1.6* 6.2* 61.8* 60* 1.8* 3.85 12.0 24.0 8.6 3.3 43.1 60* 1.5* 4.06 14.0 33.5 8.1 4.4 41.8 100 7.1 3.87 11.5 36.0 4.0 5.2 30.6 90 5.2 4.28 8.9 20.0 3.9 3.8 42.2 90 1.9 3.59 2.5* 17.4 4.8 3.5 54.2* 100 4.3 4.5

10 5.5* 13.0* 3.8 5.2 58.3* 90 3.4 3.411 4.3* 24.3 0.3* 7.9* 49.2 40* 4.0 3.712 4.3* 20.7 4.2 6.1* 48.9 90 2.6 3.113 Absent* 6.0* Absent* Absent Absent* Absent* Absent* Absent14 6.0* 11.0* 2.4* 3.0 57.9* 70* 3.0 3.7Mean (patients) 5.8 6 1.1 18.1 6 2.4 3.6 6 0.7 5.2 6 0.5 49.6 6 2.5 80 6 5 3.2 6 0.5 3.7 6 0.1Normal controls 13.6 6 7.5 42.4 6 14.9 12.9 6 4.5 4.5 6 0.8 45.9 6 4.4 100% 8.9 6 4.0 4.0 6 0.7

Group data expressed as mean 6 standard error of the mean for each parameter. Data include amplitudes for sensory nerve actionpotential (SNAP) and compound motor action potential (CMAP), distal motor latency (DML) and tibial F-wave minimum latency (min.latency). The patient number is the same as in Table 2. *Denotes an abnormal result. Normative data are shown as mean 6 standarddeviation and are taken from the sources referred to in the text. Normative data for sural SNAP amplitudes (Burke et al., 1974) and tibialCMAP amplitudes (Buschbacher, 1999) were age-matched and are shown in the table for the age groups 41–60 y and 30–59 y, respectively.



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Nerve excitability abnormalitiesbefore dialysisMotor excitability studies were successfully obtained from

TA in all patients and from EDB in 13 out of 14 patients.

The recordings from a single, representative patient are com-

pared with normal limits in Fig. 1, and mean electrotonus and

recovery cycle data are illustrated in Fig. 2A and B. Patient 13

(Table 2) had no recordable response from EDB. Pre-dialysis

abnormalities in excitability were noted in 12 out of

14 patients in the study. Stimulus–response curves for the

group (e.g. Fig. 1A) were shifted to the right in pre-dialysis

recordings from both TA and EDB when compared with

previously established normative data (Krishnan et al.,

2004), indicating that their axons were of high threshold

before dialysis. The stimulus intensity needed to produce a

CMAP 50% of maximal was significantly greater in the renal

patients for both TA and EDB recordings (TA ESKD record-

ings, 10.0 6 1.7 mA; controls, 5.7 6 0.3 mA; P < 0.005; EDB

ESKD recordings, 12.9 6 1.4 mA; controls, 6.9 6 0.3 mA;

P < 0.0005). In keeping with the length-dependent nature

of uraemic neuropathy, maximal CMAP amplitude in renal

patients, measured from onset to negative peak, was similar to

that in controls for TA recordings but significantly reduced in

EDB recordings (TA ESKD recordings, 2.4 6 0.5 mV; con-

trols, 2.4 6 0.2 mV; EDB ESKD recordings, 1.3 6 0.2 mV;

controls, 2.5 6 0.2 mV; P < 0.0005).

There was a significant reduction in tSD for EDB in the

renal patients compared with controls, although tSD was sim-

ilar in both groups in TA recordings (TA ESKD recordings,

0.41 6 0.08 ms; controls 0.43 6 0.01 ms; EDB ESKD record-

ings, 0.33 6 0.05 ms; controls 0.46 6 0.01; P < 0.0005).

Rheobase, defined as the threshold current for a stimulus

of infinitely long duration (Bostock and Rothwell, 1997;

Bostock et al., 1998), was increased in ESKD patients in both

TA and EDB recordings before dialysis (TA ESKD recordings,

7.3 6 1.8 mA; controls, 3.8 6 0.2 mA; P < 0.005; EDB ESKD

recordings, 9.7 6 1.2 mA; controls 4.5 6 0.2 mA; P < 0.0005).

Reductions in threshold electrotonus (Figs 1E and 2A) were

noted in both the depolarizing and hyperpolarizing direc-

tions, leading to a ‘fanned in’ appearance (Kiernan and

Bostock, 2000; Kaji, 2003). Depolarizing threshold electroto-

nus (TEd) at the 90–100 ms interval (TEd 90–100 ms),

previously established as a sensitive indicator of resting

membrane potential (Kiernan and Bostock, 2000), was

lower in the ESKD patients in both TA and EDB recordings

(Table 3) than in the normal controls (TA, P < 0.005; EDB,

P < 0.0005). There were similar reductions in TEd 10–20 ms

(TA, P < 0.0005; EDB, P < 0.0005) and TEd 40–60 ms (TA,

P < 0.0005; EDB, P < 0.0005). Hyperpolarizing threshold

electrotonus (TEh) was also significantly reduced in the ESKD

patients at the 10–20 ms (TA, P < 0.005; EDB, P < 0.0005) and

90–100 ms intervals (TA, P < 0.005; EDB, P < 0.0005). With

respect to the current–threshold relationship (Fig. 1C),

although the resting and minimum current–threshold slopes

were not significantly different between renal patients and

controls, there was a significant change in the hyperpolarizing

current–threshold slope (TA ESKD recordings, 0.64 6 0.02;

controls 1.24 6 0.30; P < 0.01; EDB ESKD recordings,

0.60 6 0.03; controls 1.12 6 0.12; P < 0.0005).

With respect to the recovery cycle (Figs 1F, 2B and D),

refractoriness, owing to inactivation of voltage-gated

transient Na+ channels, was significantly increased in the

renal patients (TA, P < 0.05; EDB, P < 0.005). Superexcitab-

ility, related to the depolarizing afterpotential (Barrett and

Barrett, 1982; David et al., 1992), was reduced in the ESKD

patients (Table 3) before dialysis (TA, P < 0.0005; EDB,

P < 0.0005). Late subexcitability was also reduced in

pre-dialysis recordings (TA, P < 0.05; EDB, P < 0.05).

Table 2 Demographic and clinical data: neuropathy stage, T-NSS, neuropathic symptoms and Kt/V for each patient

Patient Age Stage T-NSS Clinical symptoms Kt/V

1 17 2 1 Lower limb paraesthesiae 1.672 64 3 4 Leg weakness, leg pain, numbness in hands and feet, unsteady gait 1.663 57 2 2 Leg weakness, numbness in feet 2.374 69 2 2 Leg weakness, upper limb paraesthesiae 1.335 22 2 2 Lower limb paraesthesiae, burning feet 1.526 28 0 1 Upper limb paraesthesiae 1.327 37 2 2 Lower limb paraesthesiae, leg weakness 1.438 62 2 2 Lower limb pain, paraesthesiae 1.629 52 2 1 Numbness in feet 1.69

10 55 2 2 Lower limb paraesthesiae, leg weakness 1.4811 62 2 1 Numbness in feet 1.6712 63 3 2 Lower limb paraesthesiae, pain in feet 2.7913 69 3 2 Leg weakness, hand weakness 1.4814 52 2 2 Pain in feet, lower limb numbness 2.31

Neuropathy staged according to the following scale: Stage 0, no neuropathy (T-NSS < 2 with normal NCS); Stage 1, asymptomaticneuropathy (T-NSS = 0 with abnormalities on NCS); Stage 2, symptomatic neuropathy (T-NSS > 2 with normal NCS or T-NSS � 1 withabnormal NCS; neuropathic symptoms non-disabling); Stage 3, disabling neuropathy (T-NSS � 2 with normal NCS or T-NSS � 1 withabnormal NCS; neuropathic symptoms reported to be disabling). The maximum possible T-NSS was nine.



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Nerve excitability changesfollowing dialysisThe ‘fanned-in’ appearance of threshold electrotonus and

the reduction in superexcitability noted before the com-

mencement of haemodialysis indicate axonal depolarization

(Kiernan and Bostock, 2000). In order to explore the hypo-

thesis that these changes may be caused by a dialysable toxin

(Bostock et al., 2004), excitability studies were repeated dur-

ing and 1 h following haemodialysis. These studies revealed

significant improvement in a number of excitability paramet-

ers (Figs 2 and 3). In particular, the original abnormalities in

parameters of threshold electrotonus largely resolved during

dialysis (Table 3). The initial pre-dialysis reduction in TEd

90–100 ms improved following dialysis in both TA and EDB

recordings (TA, P < 0.0005; EDB, P < 0.0005). Qualitatively

similar changes were also observed in TEd 40–60 ms (TA,

P < 0.005; EDB, P < 0.0005) and TEh 90–100 ms (TA, P < 0.05;

EDB, P < 0.0005).

Changes were also noted in parameters of the recovery cycle

(Table 3). There was a reduction in the degree of refractori-

ness (TA, P < 0.0005; EDB, P < 0.0005) following dialysis and

a shortening of the duration of the relative refractory period

(TA, P < 0.005; EDB, P = 0.06). These changes were accom-

panied by an increase in superexcitability following dialysis

(TA, P < 0.05; EDB, P < 0.005). An increase in late sub-

excitability following dialysis was also noted (TA, P < 0.0005;

EDB, P < 0.05).

Comparison of the post-dialysis recordings with normative

data (Krishnan et al., 2004) revealed complete resolution of

the depolarization changes noted in the pre-dialysis record-

ings in all parameters of the recovery cycle (Table 3). There

were, however, persistent abnormalities in TEd 10–20 ms (TA,

P < 0.005; EDB, P < 0.005), TEh 10–20 ms (TA, P < 0.0005;

EDB, P < 0.0005) and TEh 90–100 ms in TA recordings (TA,

P < 0.05), indicating that, although improvement occurred

with dialysis, some residual impairment persisted.

Fig. 2 Comparison of threshold electrotonus (A and C) and recovery cycle (B and D) in renal patients (continuous lines with circles)before and after dialysis, with 95% confidence intervals for normal controls (broken lines). Pre-dialysis traces demonstrate ‘fanning in’of threshold electrotonus, increased refractoriness and reduced superexcitability and late subexcitability. Abnormalities have largelyresolved 1 h after dialysis.



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Correlation of symptoms,neurophysiological parametersand potential neurotoxinsThere was a close correlation between the stage of neuropathy

and nerve conduction parameters (Fig. 4A), both motor and

sensory (sural amplitude, r = 0.68; P < 0.01; superficial radial

amplitude, r = 0.59; P < 0.05; peroneal CMAP amplitude,

r = 0.74; P < 0.01; tibial CMAP amplitude, r = 0.54;

P < 0.05). Significant correlation was also noted between

T-NSS and both pre-dialysis refractoriness (r = 0.73;

P < 0.01) and pre-dialysis TEd 90–100 ms (r = �0.53;

P < 0.05) in TA recordings (Fig. 4B).

In order to further explore the basis of the pre-dialysis

excitability changes, excitability parameters were assessed in

relation to levels of potential neurotoxins, in addition to

Table 3 Mean excitability values before, during and after dialysis for recordings from TA and EDB, with normal controldata (Krishnan et al., 2004)

Before dialysis During dialysis After dialysis Normal controls

TEd 90–100 ms (TA) 33.6 6 3.1%*** 39.2 6 2.3%*** 41.9 6 2.2% 41.5 6 0.9%TEd 90–100 ms (EDB) 33.7 6 2.6%*** 40.0 6 2.3%*** 45.9 6 1.7% 46.0 6 0.9%TEd 40–60 ms (TA) 39.9% 6 3.2%** 46.6 6 2.6%** 51.3 6 2.0% 51.1 6 0.9%TEd 40–60 ms (EDB) 41.2 6 3.3%*** 47.1 6 2.9%*** 58.0 6 2.2% 55.8 6 0.9%TEh 90–100 ms (TA) �75.2 6 10.9%* �91.1 6 19.9%* �89.2 6 8.5% �108.3 6 4.3%TEh 90–100 ms (EDB) �75.2 6 11.8%*** �84.7 6 11.0%** �101.2 6 8.1% �115.2 6 3.7%Refractoriness (TA) 59.8 6 15.9%*** 55.6 6 13.6%*** 43.8 6 11.0% 31.9 6 3.5%Refractoriness (EDB) 64.7 6 17.9%*** 56.9 6 11.3%*** 33.1 6 7.5% 24.9 6 2.8%Relative refractory period (TA) 5.4 6 0.8 ms** 4.9 6 0.9 ms*** 3.8 6 0.5 ms 3.3 6 0.1 msRelative refractory period (EDB) 5.4 6 0.8 ms (NS) 4.4 6 0.6 ms*** 3.9 6 0.8 ns 3.1 6 0.07 msSuperexcitability (TA) �9.6 6 2.0%* �14.0 6 2.1% (NS) �21.2 6 2.2% �19.1 6 1.2%Superexcitability (EDB) �11.5 6 2.6%** �14.8 6 2.7%** �28.6 6 2.8% �27.6 6 1.4%Late subexcitability (TA) 5.0 6 1.7%*** 5.9 6 1.7%*** 9.4 6 3.0% 10.6 6 0.9%Late subexcitability (EDB) 4.9 6 1.6%* 7.0 6 1.7%** 13.5 6 3.5% 9.0 6 1.0%

Data are shown for depolarizing and hyperpolarizing threshold electrotonus (TEd and TEh, respectively) and recovery cycle parameters.Data are expressed as mean 6 standard error of the mean. Pre-dialysis and during dialysis measures were compared to post-dialysis valuesusing Student’s paired t-test. Significance levels are indicated as follows: *, P < 0.05; **, P < 0.005; ***, P < 0.0005.

Fig. 3 Comparison of excitability parameters recorded from TA and EDB before, during and after dialysis. (A) Depolarizing thresholdelectrotonus at 90–100 ms. (B) Superexcitability. (C) Late subexcitability. (D) Hyperpolarizing threshold electrotonus at 90–100 ms.Results are expressed as mean 6 standard error of the mean. Asterisks indicate significance (Student’s t-test: *, P < 0.05; **, P < 0.005;***, P < 0.0005; NS, not significant).



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measures of dialysis adequacy (Table 4). With respect to

pre-dialysis excitability parameters, changes in threshold

electrotonus and superexcitability correlated strongly with

pre-dialysis serum K+ (Fig. 4C). The correlations between

these excitability parameters and K+ were far greater than

those for other substances, including creatinine, urea, cal-

cium, b-2M and PTH (Table 4). Recordings were also

obtained from one patient on five separate occasions before

dialysis and a similarly close correlation was noted between

TEd 90–100 ms and serum K+ (Fig. 4D). Correlation was also

noted between pre-dialysis PTH and superexcitability in EDB

recordings (r = 0.60; P < 0.05) and this correlation was further

strengthened after allowing for the effect of K+ (Table 4).

Although correlations were noted between excitability

measures and both urea and b-2M, these correlations were

not significant after allowing for K+ (Table 4). Kt/V, a mea-

sure of dialysis adequacy, correlated poorly with changes

in TEd 90–100 ms in recordings from both TA (r = 0.30)

and EDB (r = 0.37). It is noteworthy that all patients in the

present study had a Kt/V > 1.2 (Table 2), in keeping with

current guidelines on dialysis adequacy (National Kidney

Foundation, 2001).

Fig. 4 Relationship between (A) sural amplitude and neuropathy stage, (B) pre-dialysis TEd 90–100 ms from TA and T-NSS and(C) pre-dialysis TEd 90–100 ms from TA and serum K+. (D) Relationship between pre-dialysis TEd 90–100 ms from EDB and serum K+

in a single subject, tested on five separate occasions before dialysis. All correlations were significant at the 0.05 level. Dotted lines in(C) and (D) represent 95% confidence intervals for normal controls.

Table 4 Correlation coefficients for TEd 90–100 ms, TEh 90–100 ms and superexcitability against potential neurotoxinsbefore dialysis

Mean TEd 90–100 ms TEh 90–100 ms Superexcitability

TA EDB TA EDB TA EDB

K+ (3.6–5.1) 4.9 6 0.3 �0.87*** �0.85*** 0.90**** 0.89*** 0.85*** 0.69*Creatinine (60–110) 877 6 49.1 �0.26 �0.28 0.26 0.26 0.09 0.29

0.07 0.02 �0.13 �0.11 �0.41 0.07Urea (2.9–7.1) 24.2 6 2.3 �0.68** �0.55 0.62* 0.45 0.50 0.42

�0.24 �0.02 0.03 �0.33 �0.19 �0.04b-2M (0.7–1.8) 42.7 6 4.8 �0.42 �0.66* 0.55* 0.66 0.51 0.49

0.38 �0.18 �0.06 0.20 �0.06 0.09PTH (0.5–5.0) 28.4 6 10.2 �0.33 �0.36 0.37 0.45 0.14 0.60*

�0.18 �0.43 0.29 0.62* �0.19 0.65*Ca2+ (2.25–2.58) 2.4 6 0.06 �0.26 �0.36 0.18 0.28 0.11 �0.10

0.07 �0.05 �0.30 �0.18 �0.37 �0.57

Correlation coefficients after allowing for the effect of K+ are shown in bold font. Mean serum concentrations for the group are expressed asmean 6 standard error of the mean. Normal ranges for serum concentrations are displayed in parentheses. Serum levels are expressed inmmol/l except for creatinine (mmol/l), b-2M (mg/l) and PTH (pmol/l). Significance levels: *, P < 0.05; **, P < 0.01; ***, P < 0.001;****, P < 0.0001.



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DiscussionThe present study investigated the excitability properties of

lower limb motor axons in patients with ESKD. All patients

complained of neuropathic symptoms, and in most patients

nerve conduction studies revealed changes consistent with

peripheral neuropathy. Axonal excitability was abnormal

before dialysis, with reductions in TEd and TEh at multiple

intervals, leading to a ‘fanned in’ appearance, alteration

in the hyperpolarizing current–threshold slope and less

superexcitability and late subexcitability. There was marked

improvement in excitability parameters following dialysis,

and post-dialysis excitability recordings were either approach-

ing or were within the normal range.

Clinical symptoms and nerveconduction abnormalitiesThe rate of neuropathy in the present study was 93%,

in keeping with previous studies of uraemic neuropathy,

which have demonstrated similarly high rates of neuropathy

in patients with ESKD (Ackil et al., 1981; Angus-Leppan and

Burke, 1992; Van den Neucker et al., 1998; Laaksonen et al.,

2002). The most commonly affected parameter in the present

study was sural SNAP amplitude, which was abnormal in a

higher percentage of patients than radial SNAP amplitude,

consistent with the lower limb predisposition of neuropathy.

Previous studies have demonstrated that abnormalities in late

responses, namely F-waves and H-reflexes, may be a sensitive

marker of neuropathy in patients with uraemia (Halar et al.,

1979; Panayiotopoulos and Lagos, 1980; Van den Neucker

et al., 1998; Laaksonen et al., 2002). In the present study,

although tibial F-wave minimum latency was abnormal in

43% of patients, all but one of those patients had accompany-

ing abnormalities of sensory amplitudes, suggesting that sural

nerve SNAP amplitudes are a more sensitive neurophysio-

logical indicator of neuropathy in patients with uraemia

than lower limb F-wave parameters.

Excitability abnormalities in ESKDThere were significant abnormalities in peroneal nerve

excitability before dialysis. Maximal CMAP amplitude was

reduced in EDB recordings but maintained in TA recordings,

consistent with the length-dependent predisposition of

uraemic neuropathy. In addition, there were changes in

sensitive markers of membrane potential, including threshold

electrotonus and recovery cycle parameters, suggestive of

axonal depolarization. Threshold electrotonus refers to the

threshold changes that occur in response to subthreshold

depolarizing and hyperpolarizing pulses and is sensitive

to changes in resting membrane potential (Bostock et al.,

1998). Membrane depolarization causes a ‘fanning in’

of threshold curves (Kiernan and Bostock, 2000), as was

noted in the present study in pre-dialysis recordings from

both TA and EDB. Superexcitability, as a result of the depol-

arizing afterpotential, determined in part by the level of

activation of paranodal voltage-dependent K+ channels

(Barrett and Barrett, 1982; David et al., 1995), was signific-

antly reduced before dialysis, which is also consistent with

membrane depolarization (Kiernan and Bostock, 2000).

Although a reduction in tSD (limited to EDB recordings)

before dialysis would be unexpected for axonal depolariza-

tion, the inherent variability of this excitability measure,

and its potential to vary with metabolic change, particularly

acid-base disturbances, preclude further comment (Mogyoros

et al., 1997; Baker and Bostock, 1999).

The clear improvements in excitability parameters follow-

ing dialysis noted in the present study and in a previous study

of upper limb nerve excitability in uraemic patients (Kiernan

et al., 2002b) provide a sharp contrast to the conflicting results

of studies utilizing standard nerve conduction techniques.

Although some studies have documented post-dialysis

improvements in a number of neurophysiological parameters,

including sensory nerve conduction velocity (Nielsen, 1973;

Lang and Forsstrom, 1977) and sensory and motor action

potential amplitudes (Mansouri et al., 2001), others have

found no significant changes in neurophysiological para-

meters following a single haemodialysis session (Laaksonen

et al., 2002).

Contributing factors to pre-dialysisexcitability changesThe present study detected correlations between serum K+

and threshold electrotonus parameters and superexcitability.

There was also significant correlation between T-NSS and

both pre-dialysis refractoriness and TEd 90–100 ms, with

patients with a higher T-NSS manifesting greater excitability

changes (Fig. 4B). This is the first evidence that altered axonal

membrane potential, as recorded by nerve excitability testing,

is directly related to neuropathic symptoms. Abnormalities

of serum K+ will lead to changes in membrane potential as a

result of the dependence of resting membrane potential on

the concentration gradient for K+ (Bostock et al., 2004). The

alterations in late subexcitability provide further evidence for

the contribution of K+ to the excitability abnormalities, since

subexcitability depends on the difference between the resting

potential and the K+ equilibrium potential, and actually

increases with depolarization if extracellular K+ is unchanged

(Kiernan and Bostock, 2000). The reduction in late sub-

excitability in the pre-dialysis recordings from TA and EDB

in the present study mirrors the findings of a previous study

of median nerve excitability in patients with ESKD (Kiernan

et al., 2002b). In total, these studies suggest that pre-dialysis

axonal membrane depolarization in patients with ESKD is

more probably caused through effects mediated by serum

K+ than as a consequence of a reduction in Na+/K+ pump

function (Kiernan and Bostock, 2000; Kiernan et al., 2002b).

Studies of sensory nerve excitability in ESKD are currently

under way that may provide further insights into the role of

K+ in uraemic neuropathy, given the sensory predilection

of uraemic neuropathy and the differential effects of K+ on

sensory and motor axons (Neumcke et al., 1980).



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How do the reversible changes demonstrated in the present

study lead to the more irreversible neurological changes that

characterize uraemic neuropathy? It may be argued that the

abnormalities of serum K+ noted constitute a transient

homeostatic disturbance that is rapidly corrected by dialysis

and therefore unlikely to play a major role in the development

of chronic irreversible neuropathy. Against such an argument,

prolonged exposure to hyperkalaemia in ESKD patients seems

likely, given that the post-dialysis rebound of K+ is a well-

recognized phenomenon (De Nicola et al., 2000; Ahmed

and Weisberg, 2001), with hyperkalaemia typically recurring

within 6 h of a dialysis session owing to re-equilibration

between intracellular and extracellular fluid compartments

(Blumberg et al., 1997). Such prolonged hyperkalaemia

may cause disruption of normal ionic gradients, which are

essential for axonal survival (see Bostock et al., 2004), activ-

ating damaging Ca++-mediated processes and leading to

axonal loss (Craner et al., 2004). Excitability studies focusing

on a more prolonged period between consecutive haemo-

dialysis sessions may shed further light on the duration for

which excitability remains truly ‘normal’ in ESKD patients.

It remains possible that K+ acts synergistically with another

toxin in mediating neurotoxicity, given that excitability

changes occurred even when K+ was in the upper limits

of the normal range, rather than outside normative values

(Fig. 4C). A possible candidate is PTH, which correlated

with pre-dialysis superexcitability in EDB (Table 4). A num-

ber of studies have suggested a link between PTH and neuro-

logical complications in ESKD (Slatopolsky et al., 1980;

Massry, 1987) and PTH has been shown to prolong motor

nerve conduction velocities in animal studies (Goldstein et al.,

1978). Human studies of the effect of PTH on peripheral

nerves have yielded conflicting results, with variable

changes in motor nerve conduction velocity in patients

with ESKD (Avram et al., 1978; Di Giulio et al., 1978; Schaefer

et al., 1980).

The correlation between pre-dialysis PTH and super-

excitability in EDB must be interpreted with caution for

the following reasons. First, there was no such correlation

with superexcitability in TA, or in the combined TA and

EDB data (whereas this combination strengthened the cor-

relation with K+). Second, there was no correlation between

PTH and superexcitability in EDB when pre-dialysis and post-

dialysis data were combined (whereas this combination again

strengthened the correlation with K+).

Apart from K+ and PTH, there was no evidence for an effect

on nerve excitability of the other potential toxins, including

urea and creatinine. Although these substances are easily dia-

lysed, they correlated poorly with excitability abnormalities,

after allowing for the effect of K+. The absence of any detect-

able neurotoxic effect of urea calls into question the suitability

of Kt/V, a measure based on urea (Mallick and Gokal, 1999;

Daugirdas, 2000), for determining the adequacy of a dialysis

regimen to prevent neurotoxicity. All patients in the present

study met the current guidelines for dialysis adequacy and

yet excitability was significantly abnormal before dialysis

in the majority, with all patients exhibiting symptoms of

neuropathy. Our data suggest that, at least as far as axons

are concerned, a better indication of adequate dialysis might

be the maintenance of serum K+ within normal limits between

periods of dialysis. This may require more attention to dietary

restriction of K+ intake in some patients.

AcknowledgementsA.V.K. was supported by the Australian Association of

Neurologists Research Fellowship. Grant support from the

Australian Brain Foundation, the Sylvia and Charles Viertel

Charitable Foundation and the Ramaciotti Foundation is

gratefully acknowledged.

References

Ackil AA, Shahani BT, Young RR, Rubin NE. Late response and sural

conduction studies. Usefulness in patients with chronic renal failure.

Arch Neurol 1981; 38: 482–5.

Ahmed J, Weisberg LS. Hyperkalemia in dialysis patients. Semin Dial 2001;

14: 348–56.

Angus-Leppan H, Burke D. The function of large and small nerve fibers in

renal failure. Muscle Nerve 1992; 15: 288–94.

Asbury AK. Neuropathies with chronic renal failure, hepatic disorders,

chronic respiratory insufficiency, and critical illness. In: Dyck PJ,

Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral

neuropathy. Philadelphia: WB Saunders; 1993.

Avram MM, Feinfeld DA, Huatuco AH. Search for the uremic toxin.

Decreased motor-nerve conduction velocity and elevated parathyroid

hormone in uremia. N Engl J Med 1978; 298: 1000–3.

Babb AL, Popovich RP, Christopher TG, Scribner BH. The genesis of

the square meter-hour hypothesis. Trans Am Soc Artif Intern Organs

1971; 17: 81–91.

Baker MD, Bostock H. The pH dependence of late sodium current in large

sensory neurons. Neuroscience 1999; 92: 1119–30.

Barrett EF, Barrett JN. Intracellular recording from vertebrate myelinated

axons: mechanism of the depolarizing afterpotential. J Physiol (Lond)

1982; 323: 117–44.

Blumberg A, Roser HW, Zehnder C, Muller-Brand J. Plasma potassium

in patients with terminal renal failure during and after haemodialysis;

relationship with dialytic potassium removal and total body potassium.

Nephrol Dial Transplant 1997; 12: 1629–34.

Bolton CF. Peripheral neuropathies associated with chronic renal failure.

Can J Neurol Sci 1980; 7: 89–96.

Bostock H, Baker M. Evidence for two types of potassium channel in human

motor axons in vivo. Brain Res 1988; 462: 354–8.

Bostock H, Rothwell JC. Latent addition in motor and sensory fibres of

human peripheral nerve. J Physiol (Lond) 1997; 498: 277–94.

Bostock H, Cikurel K, Burke D. Threshold tracking techniques in the study of

human peripheral nerve. Muscle Nerve 1998; 21: 137–58.

Bostock H, Walters RJ, Andersen KV, Murray NM, Taube D, Kiernan MC.

Has potassium been prematurely discarded as a contributing factor to the

development of uraemic neuropathy? Nephrol Dial Transplant 2004; 19:

1054–7.

Burke D, Skuse NF, Lethlean AK. Sensory conduction of the sural nerve

in polyneuropathy. J Neurol Neurosurg Psychiatry 1974; 37: 647–52.

Burke D, Kiernan MC, Bostock H. Excitability of human axons. Clin

Neurophysiol 2001; 112: 1575–85.

Buschbacher RM. Tibial nerve motor conduction to the abductor hallucis.

Am J Phys Med Rehabil 1999; 78: S15–20.

Cappelen-Smith C, Kuwabara S, Lin CS, Mogyoros I, Burke D. Membrane

properties in chronic inflammatory demyelinating polyneuropathy. Brain

2001; 124: 2439–47.



Dow

nloaded from


Craner MJ, Hains BC, Lo AC, Black JA, Waxman SG. Co-localization of

sodium channel Nav 1.6 and the sodium-calcium exchanger at sites of

axonal injury in the spinal cord in EAE. Brain 2004; 127: 294–303.

Daugirdas JT. Simplified equations for monitoring Kt/V, PCRn, eKt/V, and

ePCRn. Adv Ren Replace Ther 1995; 2: 295–304.

Daugirdas JT. Dialysis adequacy and kinetics. Curr Opin Nephrol Hypertens

2000; 9: 599–605.

David G, Barrett JN, Barrett EF. Evidence that action potentials activate an

internodal potassium conductance in lizard myelinated axons. J Physiol

(Lond) 1992; 445: 277–301.

David G, Modney B, Scappaticci KA, Barrett JN, Barrett EF. Electrical and

morphological factors influencing the depolarizing after-potential in rat

and lizard myelinated axons. J Physiol (Lond) 1995; 489: 141–57.

De Nicola L, Bellizzi V, Minutolo R, Cioffi M, Giannattasio P, Terracciano V,

et al. Effect of dialysate sodium concentration on interdialytic increase of

potassium. J Am Soc Nephrol 2000; 11: 2337–43.

Di Giulio S, Chkoff N, Lhoste F, Zingraff J, Drueke T. Parathormone as a

nerve poison in uremia. N Engl J Med 1978; 299: 1134–5.

Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed

in diabetics. Muscle Nerve 1988; 11: 21–32.

Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O’Brien PC, Grina LA, et al.

Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to

sural nerve morphometry. Ann Neurol 1980; 8: 590–6.

Dyck PJ, Bushek W, Spring EM, Karnes JL, Litchy WJ, O’Brien PC, et al.

Vibratory and cooling detection thresholds compared with other tests in

diagnosing and staging diabetic neuropathy. Diabetes Care 1987; 10:

432–40.

Dyck PJ, Karnes JL, O’Brien PC, Litchy WJ, Low PA, Melton LJ III. The

Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for

diagnosis and staged severity. Neurology 1992; 42: 1164–70.

Eduardo E, Burke D. The optimal recording electrode configuration for

compound sensory action potentials. J Neurol Neurosurg Psychiatr 1988;

51: 684–7.

Goldstein DA, Chui LA, Massry SG. Effect of parathyroid hormone and

uremia on peripheral nerve calcium and motor nerve conduction velocity.

J Clin Invest 1978; 62: 88–93.

Halar EM, Brozovich FV, Milutinovic J, Inouye VL, Becker VM. H-reflex

latency in uremic neuropathy: correlation with NCV and clinical findings.

Arch Phys Med Rehabil 1979; 60: 174–7.

Hegstrom RM, Murray JS, Pendras JP, Burnell JM, Scribner BH. Two year’s

experience with periodic hemodialysis in the treatment of chronic uremia.

Trans Am Soc Artif Intern Organs 1962; 8: 266–80.

Kaji R. Physiology of conduction block in multifocal motor neuropathy and

other demyelinating neuropathies. Muscle Nerve 2003; 27: 285–96.

Kanai K, Kuwabara S, Arai K, Sung JY, Ogawara K, Hattori T. Muscle cramp

in Machado-Joseph disease: altered motor axonal excitability properties

and mexiletine treatment. Brain 2003; 126: 965–73.

Kiernan MC, Bostock H. Effects of membrane polarization and ischaemia

on the excitability properties of human motor axons. Brain 2000; 123:

2542–51.

Kiernan MC, Burke D, Andersen KV, Bostock H. Multiple measures of axonal

excitability: a new approach in clinical testing. Muscle Nerve 2000; 23:

399–409.

Kiernan MC, Hart IK, Bostock H. Excitability properties of motor axons

in patients with spontaneous motor unit activity. J Neurol Neurosurg

Psychiatr 2001a; 70: 56–64.

Kiernan MC, Cikurel K, Bostock H. Effects of temperature on the excitability

properties of human motor axons. Brain 2001b; 124: 816–25.

Kiernan MC, Guglielmi JM, Kaji R, Murray NM, Bostock H. Evidence for

axonal membrane hyperpolarization in multifocal motor neuropathy with

conduction block. Brain 2002a; 125: 664–75.

Kiernan MC, Walters RJ, Andersen KV, Taube D, Murray NM, Bostock H.

Nerve excitability changes in chronic renal failure indicate membrane

depolarization due to hyperkalaemia. Brain 2002b; 125: 1366–78.

Kiernan MC, Isbister GK, Lin CS-Y, Burke D, Bostock H. Acute tetrodotoxin-

induced neurotoxicity after ingestion of puffer fish. Ann Neurol 2005;

57: 339–348.

Kimura J. Electrodiagnosis in diseases of nerve and muscle. Philadelphia:

FA Davis; 1983.

Krishnan AV, Lin CS-Y, Kiernan MC. Nerve excitability properties in lower

limb motor axons: evidence for a length-dependent gradient. Muscle Nerve

2004; 29: 645–55.

Laaksonen S, Metsarinne K, Voipio-Pulkki LM, Falck B. Neurophysiologic

parameters and symptoms in chronic renal failure. Muscle Nerve 2002; 25:

884–90.

Lang AH, Forsstrom J. Transient changes of sensory nerve functions in

uraemia. Acta Med Scand 1977; 202: 495–500.

Ma DM, Liveson JA. Nerve conduction handbook. Philadelphia: FA Davis;

1983.

Ma DM, Kim SH, Spielholz N, Goodgold J. Sensory conduction study of distal

radial nerve. Arch Phys Med Rehabil 1981; 62: 562–4.

Mallick NP, Gokal R. Haemodialysis. Lancet 1999; 353: 737–42.

Mansouri B, Adybeig B, Rayegani M, Yasami S, Behshad V. Uremic neuro-

pathy and the analysis of electrophysiological changes. Electromyogr Clin

Neurophysiol 2001; 41: 107–15.

Massry SG. Parathyroid hormone: a uremic toxin. Adv Exp Med Biol 1987;

223: 1–17.

Mogyoros I, Kiernan MC, Burke D. Strength-duration properties of human

peripheral nerve. Brain 1996; 119: 439–47.

Mogyoros I, Kiernan MC, Burke D, Bostock H. Excitability changes in human

sensory and motor axons during hyperventilation and ischaemia. Brain

1997; 120: 317–25.

National Kidney Foundation. NKF-K/DOQI clinical practice guidelines

for hemodialysis adequacy: update 2000. Am J Kidney Dis 2001; 37:

S7–64.

Neumcke B, Schwarz W, Stampfli R. Differences between K channels in motor

and sensory nerve fibres of the frog as revealed by fluctuation analysis.

Pflugers Arch 1980; 387: 9–16.

Nielsen VK. The peripheral nerve function in chronic renal failure. V.

Sensory and motor conduction velocity. Acta Med Scand 1973; 194:

445–54.

Nodera H, Bostock H, Kuwabara S, Sakamoto T, Asanuma K, Jia-Ying S, et al.

Nerve excitability properties in Charcot-Marie-Tooth disease type 1A.

Brain 2004; 127: 203–11.

Panayiotopoulos CP, Lagos G. Tibial nerve H-reflex and F-wave studies in

patients with uremic neuropathy. Muscle Nerve 1980; 3: 423–26.

Puksa L, Stalberg E, Falck B. Reference values of F wave parameters in healthy

subjects. Clin Neurophysiol 2003; 114: 1079–90.

Schaefer K, Offermann G, von Herrath D, Schroter R, Stolzel R, Arntz HR.

Failure to show a correlation between serum parathyroid hormone,

nerve conduction velocity and serum lipids in hemodialysis patients.

Clin Nephrol 1980; 14: 81–8.

Slatopolsky E, Martin K, Hruska K. Parathyroid hormone metabolism and its

potential as a uremic toxin. Am J Physiol 1980; 239: F1–12.

Van den Neucker K, Vanderstraeten G, Vanholder R. Peripheral motor and

sensory nerve conduction studies in haemodialysis patients. A study of 54

patients. Electromyogr Clin Neurophysiol 1998; 38: 467–74.

Vanholder R, De Smet R, Hsu C, Vogeleere P, Ringoir S. Uremic

toxicity: the middle molecule hypothesis revisited. Semin Nephrol 1994;

14: 205–18.

Weiss G. Sur la possibilite de rendre comparables entre eux les appareils

servant l’excitation electrique. Arch Ital Biol 1901; 35: 413–46.



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