INVITED REVIEW ABSTRACT: Neuropathy is a common complication of end-stage kidney

disease (ESKD), typically presenting as a distal symmetrical process with

greater lower-limb than upper-limb involvement. The condition is of insidious
onset, progressing over months. and has been estimated to be present in
60%–100% of patients on dialysis. Neuropathy generally only develops at
glomerular filtration rates of less than 12 ml/min. The most frequent clinical
features reflect large-fiber involvement, with paresthesias, reduction in deep
tendon reflexes, impaired vibration sense, muscle wasting, and weakness.
Nerve conduction studies demonstrate findings consistent with a general-
ized neuropathy of the axonal type. Patients may also develop autonomic
features, with postural hypotension, impaired sweating, diarrhea, constipa-
tion, or impotence. The development of uremic neuropathy has been related
previously to the retention of neurotoxic molecules in the middle molecular
range, although this hypothesis lacked formal proof. Studies utilizing novel
axonal excitability techniques have recently shed further light on the patho-
physiology of this condition. Nerves of uremic patients have been shown to
exist in a chronically depolarized state prior to dialysis, with subsequent
improvement and normalization of resting membrane potential after dialysis.
The degree of depolarization correlates with serum K⫹, suggesting that
chronic hyperkalemic depolarization plays an important role in the develop-
ment of nerve dysfunction in ESKD. These recent findings suggest that
maintenance of serum K⫹ within normal limits between periods of dialysis,
rather than simple avoidance of hyperkalemia, is likely to reduce the inci-
dence and severity of uremic neuropathy.
Muscle Nerve 35: 273–290, 2007

UREMIC NEUROPATHY: CLINICAL FEATURES

AND NEW PATHOPHYSIOLOGICAL INSIGHTS
ARUN V. KRISHNAN, MB, BS, PhD, and MATTHEW C. KIERNAN, MB, BS, PhD

Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University
of New South Wales, Barker Street, Randwick, Sydney, NSW 2031, Australia

Accepted 24 October 2006

End-stage kidney disease (ESKD) occurs when
nephrons are irretrievably impaired to the extent
that the retention of metabolic waste products, salt,
and water becomes potentially fatal.128 ESKD may
occur due to either a primary renal disorder or as a
complication of a multisystem disorder. The com-
mon causes of ESKD remain diabetes, glomerulone-
phritis, and hypertension.136 When renal function
reaches critically low levels, renal replacement ther-
apy either in the form of dialysis or transplantation is
Available for Category 1 CME credit through the AANEM at www.
aanem.org.
Abbreviations: ADH, activity-dependent hyperpolarization; CSF, cerebro-
spinal fluid; CMAP, compound muscle action potential; CTS, carpal tunnel
syndrome; EPO, erythropoietin; ESKD, end-stage kidney disease; NSS, neu-
ropathy symptom score; PTH, parathyroid hormone
Key words: end-stage kidney disease; middle molecules; peripheral neurop-
athy; potassium; uremic neuropathy
Correspondence to: M.C. Kiernan; e-mail: M.kiernan@unsw.edu.au
© 2006 Wiley Periodicals, Inc.
Published online 28 December 2006 in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/mus.20713
required in order to remove waste products and
excess fluid.
Uremic neuropathy has for many decades been
recognized as a common complication of ESKD.7,72,145
Although the advent of dialysis and transplant pro-
grams has led to reductions in the rate of severe neu-
ropathy, the prevalence of this condition remains
high.113 This review covers the clinical and electrophys-
iological features of uremic neuropathy, with a focus
on advances in understanding the pathophysiology of
this condition.
HISTORICAL ASPECTS
The possibility of peripheral neuropathy in patients
treated with hemodialysis was first raised shortly after
the introduction of the first formal hemodialysis pro-
gram.172 The first clinical documentation of neuropa-
thy was provided in 1961 in two young male patients
with hereditary interstitial nephritis and deafness.209
The development of neuropathy in these cases, how-

Uremic Neuropathy MUSCLE & NERVE March 2007 273

ever, was attributed to the underlying hereditary disor-
der, rather than viewed as a complication of ESKD.
Following this report, Asbury et al.6 provided
extensive clinical and pathological findings in four
men who developed neuropathy as a consequence of
ESKD of varying etiologies. All four patients had
clinical features of renal disease for many years be-
fore the development of neuropathy, which mani-
fested as a symmetrical length-dependent sensorimo-
tor neuropathy. Nerve biopsies established axonal
degeneration, maximal distally, with sparing of prox-
imal nerve segments and nerve roots. Moreover,
there was no evidence to suggest nerve compression,
inflammation, or the superimposition of a systemic
disease process, such as diabetes or amyloid, leading
to the conclusion that the development of neurop-
athy was a consequence of the underlying renal dis-
order.
Early clinical neurophysiological investigations in
ESKD patients demonstrated reductions in motor
nerve conduction velocity in symptomatic and
asymptomatic patients.158,185 Jebsen et al.,82 studying
the natural history of uremic neuropathy, compared
clinical and nerve conduction findings in patients
treated conservatively to those receiving dialysis ther-
apy. Whereas the development of neuropathy in the
conservatively treated group was related to deterio-
rating renal function, those patients treated with
long-term dialysis manifested improvement in both
clinical and neurophysiological parameters. Follow-
ing these early reports and in light of the increasing FIGURE 1. Prominent wasting of intrinsic hand muscles in a
patient with established uremic neuropathy. In addition to the
use of dialysis and renal transplantation therapies,
prominent wasting and resultant clinical weakness, the patient
greater attention has been focused on uremic neu- complained of numbness and had impaired proprioception.
ropathy, with numerous studies reporting high rates
of neuropathy in ESKD patients, generally relating
the development of neuropathy to the severity of
renal failure.5,20,82,107,144,146,149,158,185,187 Of particular lower-limb than upper-limb involvement. The condi-
note, studies by Nielsen144,149 –152 and Bolton et tion is of insidious onset, progressing over months,
al.20,21 in the 1970s demonstrated nerve conduction and has been noted to have a male predominance. It
slowing in clinically unaffected nerve segments, with generally only develops at glomerular filtration rates
correlation between the extent of renal impairment of less than 12 ml/min.39 The most frequent clinical
and degree of conduction slowing, as well as im- features are those of large-fiber involvement, with
provement in neurophysiological parameters follow- paresthesias, reduction in deep tendon reflexes,
ing renal transplantation. These studies provided impaired vibration sense, weakness, and muscle wast-
clinical evidence to suggest that a uremic toxin was ing (Fig. 1). In the 1970s, Nielsen144,145 demon-
responsible for the development of neuropathy in strated the presence of neuropathic symptoms in
ESKD patients, a hypothesis that was to become a over 50% of patients with ESKD. Other studies have
major focus of future neurophysiological research in demonstrated prevalence rates varying from 60% to
this condition. 100%, depending on the diagnostic criteria ap-
plied.1,23,122,191
Laaksonen et al.122 staged the clinical severity of
INCIDENCE AND CLINICAL FEATURES
uremic neuropathy in 21 ESKD patients, using a
Peripheral neuropathy in ESKD generally presents modified version of the neuropathy symptom score
as a distal symmetrical polyneuropathy with greater (NSS) developed by Dyck et al.,57,58 and combined

274 Uremic Neuropathy MUSCLE & NERVE March 2007

this assessment with results of nerve conduction
studies. The NSS quantified symptoms that were
grouped into three categories to reflect alteration in
motor, sensory, and autonomic systems. Within each
group, further subsets were used to group symptoms
according to the region affected and the presence of
positive or negative symptoms. Using the NSS and
the staging procedure previously used in studies of
diabetic patients,57,58 81% of ESKD patients received
a diagnosis of neuropathy. Stage 1 neuropathy
(asymptomatic neuropathy) was diagnosed in 19%,
stage 2 neuropathy (symptoms nondisabling) was
present in 48%, and stage 3 neuropathy (disabling
symptoms) was noted in 14%. In a more recent
study,113 93% of ESKD patients had neuropathic
symptoms on NSS testing, with 72% diagnosed with
stage 2 neuropathy and 21% with stage 3 neuropa-
thy, despite all patients meeting currently accepted
guidelines of dialysis adequacy.143
CLINICAL AND NEUROPHYSIOLOGICAL
FINDINGS IN GENERALIZED
UREMIC NEUROPATHY
Early studies of uremic neuropathy utilizing nerve
biopsy techniques revealed prominent axonal de-
generation, most severe in the distal parts of nerve
trunks. Although initial studies suggested that demy-
elination was a significant feature of uremic neurop-
athy,5,54 subsequent reviews demonstrated that de-
myelination was secondary to axonal loss and that
proximal segments of the nerves were relatively
spared.3,55,67,187 These findings supported the con-
cept that uremic neuropathy was a dying-back neu-
ropathy, with metabolic failure of the neuron caus-
ing distal axonal degeneration.55
Numerous neurophysiological series have been
undertaken in patients with uremic neurop-
athy and have demonstrated findings consistent
with a generalized neuropathy of the axonal
type.1,4,13,20,41,46,49,68,80,107,113,121,130,148,155,156,179,183,185,191
Early studies focused on motor nerve conduction pa-
rameters and demonstrated slowing of conduction ve-
locity in patients prior to the development of clinical
neuropathy.45,158 Subsequent studies demonstrated ab-
normalities of nerve conduction148 with generalized
slowing in both sensory and motor nerves, accompa-
nied by reduction in sensory response amplitudes. Mo-
tor response amplitudes tend to remain relatively pre-
served, although abnormalities in lower-limb motor
nerves were noted in some patients, accompanied by
neurogenic changes in distal lower-limb muscles on
electromyography.148,149
Uremic Neuropathy
In a recent study, amplitude of the sural sensory
nerve action potential was found to be the most sensi-
tive indicator of uremic neuropathy, being reduced in
50% of ESKD patients.113 Other groups have con-
firmed similar findings, demonstrating reductions in
sensory and motor response amplitudes in addition to
abnormalities of late responses.1,4,49,122,130,137,157,191 Re-
duction in peroneal nerve motor conduction veloc-
ity46,137,148 and prolongation of tibial F-wave minimum
latencies122 have been established as sensitive indica-
tors of neuropathy in ESKD patients. Prolongation of
soleus H reflexes has also been demonstrated in pa-
tients without clinical evidence of neuropathy, suggest-
ing that this parameter may be more sensitive in de-
tecting early neuropathy.68,191
Studies of quantitative sensory testing in ESKD
patients have demonstrated increased vibratory per-
ception thresholds, most marked in the lower
limbs,147 whereas somatosensory-evoked potentials
in ESKD patients demonstrate abnormalities of con-
duction along both the distal and proximal segments
of peripheral somesthetic pathways, but less com-
monly along intracranial sensory pathways.25,153,166
A study of single-fiber electromyography demon-
strated normal fiber densities in motor units of ESKD
patients.186 This finding suggested that reinnervation,
characterized by increased fiber density, had failed to
occur. However, this was accompanied by increased
jitter, possibly reflecting peripheral demyelination in
the setting of axonal degeneration. A further single-
fiber EMG study established that jitter abnormalities
improved following a year of dialysis.106
Early studies of nerve excitability, utilizing a lim-
ited range of excitability parameters, demonstrated
an elevated threshold for excitation even when nerve
conduction values were normal, in addition to dem-
onstrating prolongation of absolute and relative re-
fractory periods.25,125,182,208 As a consequence, it was
concluded that the safety factor for neural transmis-
sion at the nodes of Ranvier would be lowered. Un-
expectedly, uremic nerves retained vibratory percep-
tion and their sensory response amplitudes for a
longer period than control nerves when rendered
ischemic.43 Uremic nerves also behaved differently
when temperature was lowered, with a less rapid rise
in response amplitude compared to controls.24,25
In addition to the slowly progressive sensorimo-
tor axonal neuropathy, a more rapidly progressive
motor neuropathy has been described. A small num-
ber of ESKD patients with diabetes have also been
shown to develop a subacute neuropathy progress-
ing over a few months, with severe muscle weakness.
In this group of patients, nerve conduction studies
may demonstrate features of either a demyelinating
MUSCLE & NERVE March 2007 275
or axonal neuropathy.26,27,165 Although the presence
of diabetes complicates assessment of nerve conduc-
tion data, the absence of preexisting neuropathic
symptoms and the clinical improvement noted fol-
lowing dialysis or renal transplantation suggest a
metabolic basis for the neuropathy, related to the
underlying ESKD. Analysis of cerebrospinal fluid
(CSF) is rarely helpful, as CSF protein concentration
is frequently elevated in ESKD patients and may
simulate the albuminocytologic dissociation that is
characteristic of Guillain–Barré syndrome.23
Small-fiber neuropathy may develop as a clinical
entity in ESKD patients. Lindblom and Tegner124
demonstrated abnormalities of thermal sensation in
30% of ESKD patients and concluded that small-
fiber neuropathy may exist as a distinct entity in
these patients. These results, however, differed from
those of other groups who demonstrated minimal
impairment of thermal sensation in ESKD.56,188 In a
study of 20 ESKD patients, abnormalities in standard
nerve conduction studies were demonstrated in 16
patients,4 whereas abnormal thermal thresholds
were found in only 6 patients and, when present, did
not correlate with clinical evidence of polyneurop-
athy.4 Such findings are consistent with those of
pathological studies that demonstrated greater vul-
FIGURE 2. Forearm arteriovenous fistula (basilic vein transposi-
nerability of larger-diameter fibers in ESKD pa- tion) in a patient referred for neurophysiological assessment of
tients.55 right hand pain and numbness. Subsequent nerve conduction
studies established a generalized axonal neuropathy, with su-
MONONEUROPATHIES IN ESKD peradded features consistent with carpal tunnel syndrome.

Mononeuropathies are a frequent clinical complica-

tion in ESKD patients and most typically occur in the
median, ulnar, and femoral nerves.39
Carpal tunnel syndrome (CTS) is the most com-
mon mononeuropathy in ESKD, with prevalence
rates varying from 6% to 31%.15,17,52,66,67,76,81,170 ␤2-
Microglobulin amyloidosis is a major factor underly-
ing the development of CTS in ESKD patients,63 a
complication noted in patients on long-term hemo-
dialysis. Amyloid deposits have been identified in
synovial specimens from dialysis patients with CTS63
and an increase in the rate of CTS has been demon-
strated with increasing hemodialysis duration.63
Strategies geared at reducing the levels of ␤2-micro-
globulin, such as the use of high-flux biocompatible
membranes and ␤2-microglobulin adsorption col-
umns, have resulted in reduced rates of CTS devel-
opment and ultimately improvement in symp-
toms.63,118,192
Other factors that may contribute to the in-
creased incidence of CTS in ESKD patients include
uremic tumoral calcinosis47,203 and the placement of
arteriovenous fistulas (Fig. 2), inducing a “steal” of
blood from the distal limb.66,70,105,119,131,141,201 The
placement of Brescia–Cimino arteriovenous fistulas
between the radial artery and cephalic vein has been
associated with the development of both the clinical
features of CTS and subclinical neurophysiological
abnormalities in median or ulnar nerve territo-
ries.70,105 A recent study demonstrated CTS in 30.5%
of limbs with fistulas compared to 12.2% on the
contralateral side.66 Although the site of the fistula
had no effect on the development of CTS, a signifi-
cant correlation was noted between the age of the
fistula and the presence of CTS.
With regard to treatment of CTS in ESKD, the
outcome of median nerve decompression appears
inferior in this group compared to patients with
idiopathic CTS.76,102,173 In addition, recurrence rates
are higher. In ESKD patients with recurrent CTS, an
endoscopic approach may prove to be effective in
relieving persistent symptoms.211
Ulnar neuropathy is also a common occurrence
in ESKD, affecting up to 51% of patients undergoing
hemodialysis.142 Causes include external compres-

276 Uremic Neuropathy MUSCLE & NERVE March 2007

sion at the elbow during prolonged dialysis thera-
py142 and other risk factors as outlined for CTS,
particularly arteriovenous fistulas and uremic tu-
moral calcinosis.62,69
In addition to their possible contributions to the
development of CTS and ulnar neuropathy, upper-
limb arteriovenous fistulas may be associated with an
acute-onset neuropathy, first described by Bolton et
al.22 and later termed ischemic monomelic neurop-
athy.206 In this condition, acute limb ischemia devel-
ops due to shunting of arterial blood away from the
distal parts of the limb.135 The severity of ischemia
typically affects nerves, without causing changes in
other tissues such as muscle, that possess a higher
threshold for ischemic injury. Diabetic patients are
particularly vulnerable, especially those with preex-
isting peripheral vascular disease or neuropathy.162
The symptoms are those of multiple upper-limb
mononeuropathies, with distal sensory loss and
weakness in the muscles of the forearm and hand.
Electromyography demonstrates neurogenic abnor-
malities in distal limb muscles with sparing of prox-
imal musculature.206 There may be predilection for
median nerve involvement and the presence of con-
duction block in this nerve has been described as a
sign of reversible injury.87 Early ligation or revision
of the fistula frequently leads to significant clinical
and electrophysiological improvement.87,161
Femoral neuropathy in ESKD patients is a well-
recognized complication of renal transplantation,
with an incidence of ⬃2%.83,134,175 Prolonged use of
self-retaining retractors in the region of the femoral
nerve during renal transplantation may cause nerve
compression and neuropraxic injury.175 Rapid recov-
ery is expected in cases of neurapraxia but pro-
longed ischemia may lead to axonal loss.210 The
prognosis is generally favorable, with most patients
achieving complete recovery,175 although residual
deficits may be present when significant axonal loss
has occurred.134
AUTONOMIC NEUROPATHY IN ESKD
Autonomic neuropathy may develop in ESKD pa-
tients, manifesting as postural hypotension, im-
paired sweating, diarrhea, constipation, or impo-
tence.14,197 In a study of 36 ESKD patients,
gastrointestinal autonomic symptoms were evident
in 42% and impotence in 45%.200 Although postural
hypotension was an uncommon clinical finding,
36% complained of episodes of postural dizziness,
which was most prominent in elderly ESKD patients.
Some studies have suggested that autonomic neu-
ropathy occurs as a manifestation of generalized
Uremic Neuropathy
polyneuropathy,89,200 but others have shown no cor-
relation between autonomic dysfunction and periph-
eral nervous system abnormalities.44,180,195 The
mechanisms underlying the development of uremic
autonomic neuropathy remain unknown, although
an association with hyperparathyroidism has been
suggested.178,194
Studies utilizing objective measures of auto-
nomic function, including R–R interval variation
as a measure of parasympathetic function and sus-
tained handgrip and sympathetic skin response as
measures of sympathetic function, have estab-
lished abnormalities in up to 62% of ESKD pa-
tients on dialysis treatment.44,121,178,200 However,
these abnormalities frequently occur in the ab-
sence of clinical symptoms of autonomic dysfunc-
tion.59,164 Parasympathetic dysfunction has been
shown to occur with greater frequency than sym-
pathetic dysfunction, which is generally more com-
mon in diabetic ESKD patients.73,164,168,195,196,200,212
The contribution of autonomic dysfunction to
the development of intradialytic hypotension re-
mains a matter of ongoing debate, with some studies
suggesting a possible association89,168 and others sug-
gesting no significant relationship.123,195 A recent
review of the literature on the use of the oral alpha-
1-adrenoceptor agonist midodrine in the treatment
of intradialytic hypotension suggested a beneficial
effect, although the authors drew attention to the
fact that most studies were not randomized and had
small sample sizes.137
EFFECTS OF DIALYSIS AND TRANSPLANTATION
ON UREMIC NEUROPATHY
Early reports investigating the effects of hemodialysis
on uremic neuropathy suggested that some patients
with mild neuropathy recovered completely with ad-
equate dialysis.72,82,107,185 In fact, failure to improve
was considered to be an indictor of insufficient dial-
ysis. These reports, however, did emphasize that the
extent of improvement was likely to be related to the
severity of neuropathy and that patients with severe
neuropathy were unlikely to experience any signifi-
cant recovery.82,107,185
More recent studies, however, have demon-
strated that improvement in neuropathy with dialysis
is an uncommon event.13,41,151,155 Although these
studies suggest that dialysis retards the progression
of neuropathy in most patients, in some cases a
gradual deterioration of neuropathy may oc-
cur.13,41,151,155 A comparison of hemodialysis and
peritoneal dialysis with regard to neuropathy pro-
MUSCLE & NERVE March 2007 277
gression has demonstrated no significant difference
between the two dialysis forms.184
Renal transplantation remains the only known
cure for uremic neuropathy,20,21 with clinical im-
provement in sensory and, to a lesser extent, motor
function occurring within a few days of transplanta-
tion.80 Serial nerve conduction studies following
transplantation demonstrated a correlation between
the improvement in nerve conduction and biochem-
ical parameters, suggesting that metabolic phenom-
ena may underlie the rapid improvement.156 Even
with severe neuropathy, improvement in symptoms
and signs may occur within 1 month of transplanta-
tion, although in some patients the recovery is pro-
longed or remains incomplete.21,152,183
Dialysis and transplantation are less beneficial for
patients with autonomic neuropathy compared to
large-fiber neuropathy. An early study suggested that
autonomic function may be improved with dialysis,74
but a more recent report failed to show any signifi-
cant benefit.198 Although renal transplantation may
lead to improvement or normalization of autonomic
function,127,164 the time course of such improvement
is often slow and may be incomplete, with significant
changes often occurring after 4 – 8 years.177,199
Recent evidence suggests that treatment with
erythropoietin (EPO) may prove beneficial in ESKD
patients with neuropathy71,174 as well as for patients
with neuropathy due to other etiologies.91,189 Treat-
ment with EPO improved motor nerve conduction
velocity in ESKD patients, but had no effect on sen-
sory indices. In vitro studies have shown that EPO
receptors are present on Schwann cells and in dorsal
root ganglion neurons.79,90 Upregulation of EPO re-
ceptors occurs after axonal injury, mediated by re-
lease of nitric oxide, and administration of exoge-
nous EPO is associated with reduction in limb
weakness and neuropathic pain behavior.90
DIALYZABLE TOXINS AND THE
MIDDLE MOLECULE HYPOTHESIS
Hegstrom et al.72 postulated that uremic neuropathy
occurred due to accumulation of a dialyzable sub-
stance on the basis of their observational studies that
demonstrated improvement in neuropathy in two
subjects with long-standing ESKD following com-
mencement of dialysis therapy. Later studies demon-
strated that patients treated with peritoneal dialysis
had lower rates of uremic neuropathy despite the
fact that these patients frequently had higher blood
urea and creatinine concentrations.10 The lower
neuropathy rate in the peritoneal dialysis group was
thought to indicate that the substance responsible
278 Uremic Neuropathy
for neuropathy was better dialyzed by the perito-
neum than by the cellophane membranes used in
hemodialysis. On this basis, the most likely group of
substances was thought to be the “middle mole-
cules,” substances with a molecular weight of 300 –
12,000 Da,193 given that such substances were known
to be poorly cleared by hemodialysis membranes.
Marked elevations in the concentrations of mid-
dle molecules have been demonstrated in ESKD pa-
tients, a finding not observed in healthy controls.60,61
Examples of such molecules include parathyroid
hormone (PTH) and ␤-2-microglobulin (␤-2M), the
levels of which are elevated in patients with ESKD.193
Further studies demonstrated that the use of thinner
dialysis membranes and longer dialysis times, strate-
gies that would have greater benefits for the clear-
ance of middle molecules compared to small mole-
cules, led to significant reductions in the rates of
severe neuropathy.9,64 A study using a hemodialysis
membrane highly permeable to middle molecules
also demonstrated a dramatic reduction in the de-
velopment of neuropathy.129
These early studies, however, were hampered by
a number of difficulties, not least of which was the
inability to measure middle molecule levels.10 An-
other major shortcoming of the hypothesis has been
the lack of conclusive evidence that any single mol-
ecule in the middle molecular range is actually neu-
rotoxic.104,193 In a study of nerve conduction velocity
following renal transplantation, correlation was
noted between the postoperative concentration of
myoinositol, a middle molecule, and median nerve
sensory conduction velocity.156 Although myoinosi-
tol levels are elevated in ESKD patients, there is little
convincing evidence for a neurotoxic effect.193,207
The only middle molecule for which some evi-
dence of neurotoxicity exists is PTH, with some studies
suggesting a link between PTH and the neurological
complications of ESKD.132,176 PTH has been shown to
prolong motor nerve conduction velocities in animal
studies,65 although human studies of the effect of PTH
on peripheral nerves have yielded conflicting results,
with variable changes in motor nerve conduction ve-
locity in patients with ESKD.8,53,169
Despite the shortcomings of the middle molecule
hypothesis, the hypothesis that a dialyzable toxin
may be involved in the pathophysiology of this con-
dition remains prevalent. More recently, it has been
suggested that the following criteria should be met
in order for a substance to be truly regarded as a
uremic neurotoxin: (1) it must be an identifiable
chemical; (2) it should be elevated in the blood of
uremic patients; (3) there should be a direct positive
relationship between blood level and neurological
MUSCLE & NERVE March 2007
FIGURE 3. (A) Saltatory conduction, with the action potential jumping from one node of Ranvier to the next. (B) Different channels are
distributed unevenly along the axonal membrane: Na⫹ channels are found in high concentrations at the node, as are slow K⫹ channels.
Fast potassium channels (K⫹f) are almost exclusively paranodal. Inward rectifier channels (Ih), permeable to both K⫹ and Na⫹ ions act
to limit axonal hyperpolarization, whereas the Na⫹/K⫹ pump serves to reverse ionic fluxes that may be generated through activity.
dysfunction; (4) it should cause neurological dys-
function in animals at appropriate blood levels; and
(5) its removal from the blood should abolish the
dysfunction.38 The middle molecule hypothesis fails
to satisfy a number of these criteria, most impor-
tantly criterion 3, as there is very little evidence to
suggest that such molecules are actually neurotoxic.
Despite the evidence that a dialyzable toxin may
underlie the development of uremic neuropathy,
the mechanism of this neurotoxicity remained un-
clear. The possibility that the neurotoxic effect may
be due to alteration in membrane excitability was
first proposed by Nielsen who, drawing on evidence
from in vitro studies of muscle and red blood cells in
ESKD patients,18,205 proposed that one or more of
these toxins may cause neuropathy by inhibiting ac-
tivity of the axonal Na⫹/K⫹ pump. This energy-
dependent pump is electrogenic, with three Na⫹
ions being pumped out for every two K⫹ ions
pumped into the axon,159 leading to a net deficit of
positive charge on the inner aspect of the axonal
membrane. Paralysis of the Na⫹/K⫹ pump abolishes
the direct contribution of the hyperpolarizing pump
current to the membrane potential and leads to an
accumulation of extracellular K⫹ that causes further
depolarization.84,163 The Na⫹/K⫹ pump is therefore
of critical importance in maintaining normal ionic
gradients, which are essential for axonal survival.
Disruption of these gradients may cause reverse op-
eration of the Na⫹/Ca2⫹exchanger, leading to in-
creased levels of intracellular Ca2⫹ and axonal loss.48
Although it is not possible to measure membrane
potential directly in human axons in vivo, indirect
Uremic Neuropathy
information regarding membrane potential and ax-
onal ion function may be gained from nerve excit-
ability studies.37,40 Axonal excitability can be investi-
gated using threshold tracking, where “threshold”
indicates the stimulus current required to produce a
target potential that can be adjusted online by com-
puter (i.e., tracked) to assess excitability. The recent
development of automated protocols has facilitated
the use of excitability techniques in the clinical set-
ting.93,95,108 Rather than relying on a single parame-
ter, excitability techniques provide information re-
garding alterations in membrane potential and
axonal ion channel function based on coherent
changes in a number of different indices. Nerve
excitability measures have been used to study periph-
eral nerves in patients with neuropathy and have
provided information about disease pathophysio-
logy.42,85,88,96,110,111,120 Prior to discussing the
changes in axonal excitability that develop in pa-
tients with ESKD, a general understanding of nerve
physiology is critical for the further discussion re-
lated to the pathophysiological mechanisms involved
in the development of neuropathy.
MOLECULAR STRUCTURE OF THE AXON
AND SALTATORY CONDUCTION
Transmission of impulses in myelinated axons oc-
curs by means of saltatory conduction (Fig. 3), with
action potentials advancing between successive
nodes of Ranvier:
“Like a kangaroo travelling at speed, the action
potential advances at near-uniform velocity, but it
MUSCLE & NERVE March 2007 279
 is powered by discrete kicks of inward membrane old current for a target potential declines as the
current at nodes of Ranvier.”33 stimulus duration is increased.28,138,139,204 Calcula-
tion of ␶SD in human subjects may be performed
The chief role of the axon is that of impulse conduc- using the ratio between the stimulus–response
tion, which depends on the electrical cable structure curves for two different stimulus durations using
and voltage-dependent ion channels of the axonal Weiss’ formula,204 shown below for threshold cur-
membrane. Much of the knowledge about axonal rents for stimuli of 0.2 ms (I 0.2) and 1.0 ms (I 1.0)
membrane structure and ion channel function comes duration:
from studies in nonmammalian axons (squids, verte-
brates). Only over the last few decades have techniques
␶SD ⫽ 0.2共I 0.2 –I 1.0 兲/关I 1.0 –共0.2 ⫻ I 0.2 兲兴
such as patch-clamping allowed investigation of mam-
malian axons, and only over more recent years have
Both strength– duration time constant and rheobase
human axons been studied in vitro.
(the threshold for a stimulus of infinitely long dura-
In myelinated axons from peripheral nerve,
tion) are properties of the nodal membrane, depen-
voltage-sensitive Na⫹ channels are clustered at high
dent on passive membrane properties and a local re-
densities (up to 1,000/␮m2) in the nodal axon, com-
sponse mediated by persistent Na⫹ channels.36
pared to the internodal region (25/␮m2).202 The
Alterations in membrane potential will affect both pa-
high density of Na⫹ channels at the node reflects the
rameters, with depolarization leading to prolongation
need of saltatory conduction for a large inward cur-
of strength– duration time constant and reduced rheo-
rent at the node (Fig. 3). When the nodal membrane
base; and hyperpolarization causing a shorter
is depolarized, an inward current is established, car-
strength– duration time constant and increased rheo-
ried by Na⫹ ions. The Na⫹ conductance is voltage
base. When measured in isolation, strength– duration
sensitive and regenerative: it increases with depolar-
time constant, however, is of limited utility as a marker
ization, and this in turn leads to greater depolariza-
of membrane potential, as it is also affected by other
tion as well as depolarization of the next node.75 This
factors including demyelination and discrete changes
explosive process would end with the whole axon
in nodal Na⫹ conductances.28,100
depolarized, were it not that the Na⫹ channels im-
Threshold electrotonus is the only clinical tech-
mediately started closing again, due to Na⫹ channel
nique available to assess alterations in both nodal
inactivation.
and internodal conductances. This method mea-
Na⫹ channels are membrane-spanning protein
sures the threshold changes produced by long-dura-
molecules, containing a pore unit (␣-subunit)
tion depolarizing and hyperpolarizing currents.30,37
through which Na⫹ ions can diffuse almost freely in
These conditioning polarizing currents are set to
the open state.171 The fast activation process (from
defined percentages of the unconditioned threshold
resting closed to open state) and the slower inacti-
current, but importantly remain subthreshold in
vation process (from open to inactivated state) con-
that they do not trigger an action potential.37 The
sist of conformational changes by the channel pro-
response of the threshold current to the subthresh-
tein, both driven by the changes in voltage gradient
old conditioning currents is tested at varying condi-
across it. A variety of toxins and drugs bind to the
tioning–test intervals before, during, and after the
␣-subunits of Na⫹ channels. Most toxins bind to sites
conditioning currents. By convention, threshold
that are involved in activation and inactivation, ex-
changes are plotted as threshold reductions (see
cept for tetrodotoxin and its derivatives that occlude
Figs. 5, 6), such that depolarizing responses are plot-
the outer pore of the Na⫹ channel.100,154 Some of
ted in an upward direction and hyperpolarizing re-
these binding sites are also the target of mutation in
sponses in a downward direction. In addition to
hereditary Na⫹ channelopathies.101
providing information regarding internodal conduc-
tances, threshold electrotonus is also sensitive to
ASSESSMENT OF NERVE EXCITABILITY IN A
changes in axonal membrane potential,11,92 with
CLINICAL SETTING
membrane depolarization causing a “fanning-in” ap-
Assessment of nerve excitability using automated pearance of threshold electrotonus,86 whereas hy-
protocols (Fig. 4) includes assessment of both nodal perpolarization leads to a “fanning-out” (Fig. 5).
and internodal axonal properties. The activity of Information regarding axonal ion channel func-
nodal persistent Na⫹ conductances may be assessed tion may also be gained through assessment of re-
by measurement of the strength– duration time con- covery cycle parameters. Following conduction of a
stant and rheobase. The strength– duration time single impulse, myelinated axons go through a ste-
constant (␶SD) refers to the rate at which the thresh- reotypical series of excitability changes known as the

280 Uremic Neuropathy MUSCLE & NERVE March 2007

FIGURE 4. (A) Arrangement for nerve excitability studies in ESKD patients undergoing hemodialysis. The current required to produce the
desired compound motor action potential (CMAP) amplitude is determined using a computerized threshold-tracking program that is run
by a personal computer. Recordings are amplified and digitized using an analog-to-digital board. Stimulus waveforms are converted to
current with a purpose-built isolated linear bipolar constant current stimulator. The threshold tracking software consists of an automated
tracking system in which the amplitude of the test stimulus is automatically increased or decreased by a percentage step after each
response, depending on the difference between the recorded response and the target response, generally set to 40% of maximal CMAP
amplitude for motor axons, as shown in (B). The protocol incorporates a proportional tracking system, in which the change in the stimulus
is proportional to the difference between the actual and target responses.

recovery cycle (Figs. 5, 6). For a period of 0.5–1.0 ms
after an impulse, axons are completely inexcitable
and cannot generate another impulse regardless of
the strength of the depolarizing stimulus. This pe-
riod is known as the absolute refractory period. The
axon then enters a period of relative refractoriness
that can be measured either as the increase in cur-
rent required to produce a potential of a specified
size, known as refractoriness, or as the duration of
the relative refractory period until threshold has
returned to baseline, usually 3– 4 ms.
This period of refractoriness is followed by a
period of superexcitability (or supernormality), dur-
ing which there is a reduction in threshold occurring
over a 10 –15-ms interval. Finally, there is a late phase
of raised threshold known as late subexcitability,
ending around 100 ms. These changes in threshold
are associated with changes in latency, which is in-
creased during the refractory period, decreased dur-
ing superexcitability, and increased during late sub-
excitability.16,181
The relative refractory period results from in-
activation of nodal transient Na⫹ channels. It is
prolonged by membrane depolarization and re-
duced by hyperpolarization. Refractoriness may
therefore be used a measure of membrane poten-
tial, although it is essential to take into account
the effect of temperature, given that cooling leads
to an increase in refractoriness.94 Furthermore,
measures of refractoriness may be unreliable in
situations of impaired distal transmission, as may
occur with axonal demyelination, neuromuscular
junction abnormalities, muscle disease, or any
other factor that reduces the security of impulse

Uremic Neuropathy MUSCLE & NERVE March 2007 281

FIGURE 5. Six plots of excitability parameters recorded from tibialis anterior for a single representative patient (continuous lines with
circles) prior to dialysis with 95% confidence intervals (broken lines) for a single subject.95 (A) Absolute stimulus–response relationship
for stimuli 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 curve
corresponds to the threshold for a CMAP 50% of maximum and the broken ellipse corresponds to the 95% confidence limits for a single
subject. (B) Normalized stimulus–response relationship. (C) Current–threshold relationship, reflecting rectifying properties of the axon
following polarizing currents. Threshold changes to hyperpolarizing current are represented on the left and to depolarizing current on the
right. (D) Distribution of strength– duration time constants of nine populations of axons, from 5% to 95% of maximal CMAP in groups of
10%. (E) Threshold electrotonus. Changes are plotted as threshold reductions, with depolarization represented in an upward direction and
hyperpolarization in a downward direction. (F) Recovery cycle, showing the relative refractory period, superexcitability, and late
subexcitability. There is “fanning-in” of threshold electrotonus,76,82 an increase in refractoriness, and reductions in superexcitability and
late subexcitability (reproduced with permission from Oxford University Press; Krishnan et al.,113 fig. 1).

transmission.37,114,120,190 Alteration in refractori- Na⫹ conductances.100,103,126 In a recent study, an

ness may also occur secondary to changes in nodal increase in refractoriness was demonstrated in pa-
Na⫹ conductances. Reductions in refractoriness tients treated with the chemotherapeutic agent
have been demonstrated in diabetic and toxic neu- oxaliplatin, in the absence of significant changes
ropathies, consistent with a reduction in the nodal in other excitability parameters, suggesting that

282 Uremic Neuropathy MUSCLE & NERVE March 2007

FIGURE 6. Comparison of threshold electrotonus (A,C) and recovery cycle (B,D) in ESKD patients (continuous lines with circles) pre- and
postdialysis, with 95% confidence intervals for normal controls (broken lines). Predialysis traces demonstrate “fanning-in” of threshold
electrotonus, increased refractoriness, and reduced superexcitability and late subexcitability. Abnormalities have largely resolved 1 h
postdialysis (reproduced with permission from Oxford University Press; Krishnan et al.,113 fig. 2).

the neurotoxicity of this agent may be mediated by
blockage of nodal transient Na⫹ channels.110
Superexcitability is due to a depolarizing afterpo-
tential that results from the capacitative charging of
the internode by the action potential12 and subse-
quently discharges through high resistance pathways
under or through the myelin sheath.40,99 Recent
studies have also suggested that activation of nodal
Na⫹ conductances may be a further contributing
factor.133 As for refractoriness, superexcitability also
varies with membrane potential, with depolarization
leading to a reduction in superexcitability and hy-
perpolarization causing an increase. Late subexcit-
ability is determined by activation of nodal slow K⫹
channels and the difference between membrane po-
tential (Er) and the K⫹ equilibrium potential (Ek)
and increases with depolarization if extracellular K⫹
is unchanged. It may therefore be used to differen-
tiate between pure depolarization and depolariza-
tion secondary to nerve ischemia in which there is no
significant change in late subexcitability due to com-
pensatory changes in extracellular K⫹ ions.92
NERVE EXCITABILITY STUDIES IN ESKD
Nerve excitability studies in ESKD patients (Fig. 4)
have recently demonstrated significant alterations in
membrane potential prior to hemodialysis, with re-
covery in the postdialysis period.97,113,115–117 Prior to
dialysis, measures of nerve excitability were signifi-
cantly abnormal in ESKD patients compared to con-
trol data.93,95,108 Stimulus–response curves were
shifted to the right, indicating that axons were of
high threshold. This was accompanied by a fan-

Uremic Neuropathy MUSCLE & NERVE March 2007 283


FIGURE 7. Relationship between predialysis depolarizing thresh-
old electrotonus at the 90 –100 ms interval (TEd 90 –100ms) and
K⫹ for pooled data from median sensory studies (open square)
and lower-limb motor studies (TA: filled diamond; EDB, open
diamond).113,117
ning-in of threshold electrotonus curves,86,92 which
assess alterations in both nodal and internodal con-
ductances and are sensitive indicators of change in
membrane potential (Figs. 5, 6). Measurement of
recovery cycles of excitability demonstrated that re-
fractoriness, due to inactivation of voltage-gated
transient Na⫹ channels, was increased and superex-
citability, due to the depolarizing afterpotential,12
was reduced. The findings were consistent with pre-
dialysis axonal depolarization in ESKD patients.92
Measures of motor and sensory nerve excitability
have been assessed in relation to changes in serum
levels of potential neurotoxins, including K⫹, Ca2⫹
urea, uric acid, and middle molecules such as PTH
and ␤-2M. Predialysis excitability abnormalities were
noted to be strongly correlated with serum K⫹ in all
studies, suggesting that hyperkalemic depolarization
may underlie the development of uremic neuropa-
thy (Fig. 7). Furthermore, abnormalities of excitabil-
ity became apparent with serum K⫹ concentrations
in the high normal range, well below the levels re-
quired to produce cardiac toxicity.38,115 The excit-
ability abnormalities in ESKD patients were also dif-
ferent from those noted in patients with diabetic
neuropathy,111 another common metabolic neurop-
athy, suggesting that the abnormalities noted in
ESKD patients were not purely a consequence of
structural changes.
Predialysis excitability recordings also demon-
strated an apparently paradoxical reduction in late
subexcitability, determined in part by nodal slow K⫹
channels. Since late subexcitability depends on the
difference between the resting potential and the K⫹
equilibrium potential and actually increases with de-
polarization if extracellular K⫹ is unchanged, the
reduction in this parameter was thought to provide
further evidence that predialysis axonal membrane
depolarization in patients with ESKD was due to
effects mediated by serum K⫹.97,113
284 Uremic Neuropathy
Potassium satisfies criteria that have been sug-
gested for a substance to be accepted as a uremic
neurotoxin.38 It is an identifiable chemical that is
elevated in the serum of ESKD patients and causes
neurological dysfunction in both humans and ani-
mals. It is also a critical determinant of axonal rest-
ing membrane potential.97 Moreover, a direct rela-
tionship exists between serum levels of K⫹ and
neurophysiological parameters, and its removal
leads to considerable improvement in these indi-
ces.97,113,115,117 The resting potentials of both nerve
and muscle membranes are largely determined by
K⫹, with relative changes in K⫹ capable of depolar-
izing membranes.
It may be argued that the abnormalities of serum
K⫹ noted in excitability studies are the consequence
of a transient homeostatic disturbance, rapidly cor-
rected by dialysis, and therefore unlikely to play a
major role in the development of chronic irrevers-
ible neuropathy. Against such an argument, pro-
longed exposure to hyperkalemia in ESKD patients
seems likely, given that postdialysis rebound of K⫹ is
a well-recognized phenomenon,2,51 with hyperkale-
mia typically recurring within 6 h of a dialysis session
due to reequilibration between intracellular and ex-
tracellular fluid compartments.19 Such prolonged
hyperkalemia may cause disruption of normal ionic
gradients and activate damaging Ca⫹⫹-mediated
processes, leading to axonal loss.48 Furthermore,
given the importance of K⫹ in mediating these ab-
normalities, current measures of dialysis adequacy,50
which are based solely on blood urea concentrations,
may be inappropriate for determining the adequacy
of a dialysis regimen to prevent neurotoxicity. A
better indication of adequate dialysis might be the
maintenance of serum K⫹ within normal limits be-
tween periods of dialysis, which may require more
attention to dietary restriction of K⫹ intake in some
patients.113
AXONAL NAⴙ/Kⴙ PUMP FUNCTION
IN ESKD PATIENTS
Inhibition of the Na⫹/K⫹ pump by uremic neurotox-
ins, previously proposed as the mechanism underlying
the development of uremic neuropathy,148 may induce
membrane depolarization.16,31,32,35,92 Of further rele-
vance, previous studies have demonstrated that alter-
ations in membrane potential and intra- and extracel-
lular K⫹ concentration have a direct effect on Na⫹/K⫹
pump function.78,77,109,140,159,160
Nerve excitability measurements provide a means
of detecting changes in membrane potential caused
by activation of the Na⫹/K⫹ pump.29,34,98 Vagg et
MUSCLE & NERVE March 2007
 the highly depolarized levels of the ischemic period.
Importantly, however, the rapid return of threshold
to baseline levels in the postischemic period con-
firmed that the Na⫹/K⫹ pump was functioning well
in ESKD.

CONCLUSION

Neuropathy is a common complication of ESKD,

occurring in the majority of patients undergoing
dialysis. At present, renal transplantation remains
the only known cure for uremic neuropathy.20,21
Recent nerve excitability studies have suggested that
hyperkalemia may underlie the development of neu-
ropathy and have argued against any dysfunction of
the axonal Na⫹/K⫹ pump in the development of
this condition. Excess K⫹ fits the profile of the neu-
rotoxin responsible for uremic neuropathy better
FIGURE 8. Comparison of excitability changes following maximal than middle molecules, parathyroid hormone, or
voluntary contraction in ESKD patients predialysis (filled dia- any other organic substance that has been previously
mond) and normal controls (open diamond). The filled arrow
indicates the time of contraction. (A) Changes in normalized
linked to the development of uremic neuropathy.
threshold for a 1-ms stimulus duration. (B) Strength– duration Recent findings from nerve excitability studies in
time constant, ␶SD. (C) Superexcitability. (D) Submaximal CMAP ESKD patients suggest that maintenance of serum
amplitude. Threshold and CMAP amplitude changes are normal-
ized to precontraction values and are expressed as mean data ⫾
SEM. Although baseline superexcitability was significantly less in
ESKD patients, there were no significant differences between
patients and controls in the magnitude of excitability changes
induced by activity,99 arguing against Na⫹/K⫹ pump dysfunction
in this condition (reprinted with permission from International
Federation of Clinical Neurophysiology; Krishnan et al.,115 fig. 3).

al.190 showed that the activity-dependent hyperpolar-

ization (ADH) of motor axons induced by voluntary
activity causes threshold changes that can be used to
assess Na⫹/K⫹ pump function. Assessment of activ-
ity-dependent excitability changes prior to hemodi-
alysis in 10 ESKD patients demonstrated quantita-
tively similar changes in ESKD patients and controls,
arguing against any significant reduction in the ax-
onal Na⫹/K⫹ pump in ESKD (Fig. 8).115
A further study also assessed Na⫹/K⫹ pump func-
tion in six ESKD patients prior to dialysis by moni-
toring the excitability changes that occurred before,
during, and after 13 min of nerve ischemia.116 With
the onset of ischemia, a short-lived threshold reduc-
FIGURE 9. Excitability parameters recorded from tibialis anterior
tion was followed by a rapid increase in threshold
for ESKD patients and controls before, during, and after the
(Fig. 9). Whereas normal controls manifested a post- ischemic period (indicated by filled horizontal bar). Mean data ⫾
ischemic threshold increase due to increased activity SEM. During ischemia refractoriness increased and superexcit-
of the Na⫹/K⫹ pump and consequent membrane ability decreased in both groups, consistent with axonal depolar-
hyperpolarization,112 a paradoxical reduction in ization. The reversal of these changes in the postischemic period
is consistent with axonal hyperpolarization. There is a smaller
threshold was noted in ESKD patients. This pattern
threshold reduction during ischemia in ESKD patients and a
suggested that the axonal Na⫹/K⫹ pump had a sta- prominent ischemic threshold increase beyond baseline values, a
bilizing effect on the axon and was attempting to feature not observed in control subjects (reproduced with permis-
return membrane potential toward baseline from sion from Oxford University Press; Krishnan et al.,116 fig. 3).

Uremic Neuropathy MUSCLE & NERVE March 2007 285

K⫹ within normal limits between periods of dialysis,
rather than simple avoidance of hyperkalemia, is
likely to reduce the incidence and severity of uremic
neuropathy.
Grant support was received from the Australian Brain Founda-
tion, Sylvia and Charles Viertel Charitable Foundation, National
Health and Medical Research Council of Australia and the Aus-
tralian Association of Neurologists. We thank Hugh Bostock and
David Burke for help in the development of the excitability stud-
ies, and Bruce Pussell and John Charlesworth for assistance in
studies in uremic patients.
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