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Kiernan 2006 (Insidence, Clinical Features, Neurophysiological)
Kiernan 2006 (Insidence, Clinical Features, Neurophysiological)
Kiernan 2006 (Insidence, Clinical Features, Neurophysiological)
Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University
of New South Wales, Barker Street, Randwick, Sydney, NSW 2031, Australia
End-stage kidney disease (ESKD) occurs when required in order to remove waste products and
nephrons are irretrievably impaired to the extent excess fluid.
that the retention of metabolic waste products, salt, Uremic neuropathy has for many decades been
and water becomes potentially fatal.128 ESKD may recognized as a common complication of ESKD.7,72,145
occur due to either a primary renal disorder or as a Although the advent of dialysis and transplant pro-
complication of a multisystem disorder. The com- grams has led to reductions in the rate of severe neu-
mon causes of ESKD remain diabetes, glomerulone- ropathy, the prevalence of this condition remains
phritis, and hypertension.136 When renal function high.113 This review covers the clinical and electrophys-
reaches critically low levels, renal replacement ther- iological features of uremic neuropathy, with a focus
apy either in the form of dialysis or transplantation is on advances in understanding the pathophysiology of
this condition.
Available for Category 1 CME credit through the AANEM at www.
aanem.org. HISTORICAL ASPECTS
Abbreviations: ADH, activity-dependent hyperpolarization; CSF, cerebro-
spinal fluid; CMAP, compound muscle action potential; CTS, carpal tunnel The possibility of peripheral neuropathy in patients
syndrome; EPO, erythropoietin; ESKD, end-stage kidney disease; NSS, neu- treated with hemodialysis was first raised shortly after
ropathy symptom score; PTH, parathyroid hormone
Key words: end-stage kidney disease; middle molecules; peripheral neurop- the introduction of the first formal hemodialysis pro-
athy; potassium; uremic neuropathy gram.172 The first clinical documentation of neuropa-
Correspondence to: M.C. Kiernan; e-mail: M.kiernan@unsw.edu.au
thy was provided in 1961 in two young male patients
© 2006 Wiley Periodicals, Inc.
Published online 28 December 2006 in Wiley InterScience (www.interscience.
with hereditary interstitial nephritis and deafness.209
wiley.com). DOI 10.1002/mus.20713 The development of neuropathy in these cases, how-
dysfunction; (4) it should cause neurological dys- information regarding membrane potential and ax-
function in animals at appropriate blood levels; and onal ion function may be gained from nerve excit-
(5) its removal from the blood should abolish the ability studies.37,40 Axonal excitability can be investi-
dysfunction.38 The middle molecule hypothesis fails gated using threshold tracking, where “threshold”
to satisfy a number of these criteria, most impor- indicates the stimulus current required to produce a
tantly criterion 3, as there is very little evidence to target potential that can be adjusted online by com-
suggest that such molecules are actually neurotoxic. puter (i.e., tracked) to assess excitability. The recent
Despite the evidence that a dialyzable toxin may development of automated protocols has facilitated
underlie the development of uremic neuropathy, the use of excitability techniques in the clinical set-
the mechanism of this neurotoxicity remained un- ting.93,95,108 Rather than relying on a single parame-
clear. The possibility that the neurotoxic effect may ter, excitability techniques provide information re-
be due to alteration in membrane excitability was garding alterations in membrane potential and
first proposed by Nielsen who, drawing on evidence axonal ion channel function based on coherent
from in vitro studies of muscle and red blood cells in changes in a number of different indices. Nerve
ESKD patients,18,205 proposed that one or more of excitability measures have been used to study periph-
these toxins may cause neuropathy by inhibiting ac- eral nerves in patients with neuropathy and have
tivity of the axonal Na⫹/K⫹ pump. This energy- provided information about disease pathophysio-
dependent pump is electrogenic, with three Na⫹ logy.42,85,88,96,110,111,120 Prior to discussing the
ions being pumped out for every two K⫹ ions changes in axonal excitability that develop in pa-
pumped into the axon,159 leading to a net deficit of tients with ESKD, a general understanding of nerve
positive charge on the inner aspect of the axonal physiology is critical for the further discussion re-
membrane. Paralysis of the Na⫹/K⫹ pump abolishes lated to the pathophysiological mechanisms involved
the direct contribution of the hyperpolarizing pump in the development of neuropathy.
current to the membrane potential and leads to an
accumulation of extracellular K⫹ that causes further MOLECULAR STRUCTURE OF THE AXON
depolarization.84,163 The Na⫹/K⫹ pump is therefore AND SALTATORY CONDUCTION
of critical importance in maintaining normal ionic
Transmission of impulses in myelinated axons oc-
gradients, which are essential for axonal survival.
curs by means of saltatory conduction (Fig. 3), with
Disruption of these gradients may cause reverse op-
action potentials advancing between successive
eration of the Na⫹/Ca2⫹exchanger, leading to in-
nodes of Ranvier:
creased levels of intracellular Ca2⫹ and axonal loss.48
Although it is not possible to measure membrane “Like a kangaroo travelling at speed, the action
potential directly in human axons in vivo, indirect potential advances at near-uniform velocity, but it
recovery cycle (Figs. 5, 6). For a period of 0.5–1.0 ms are associated with changes in latency, which is in-
after an impulse, axons are completely inexcitable creased during the refractory period, decreased dur-
and cannot generate another impulse regardless of ing superexcitability, and increased during late sub-
the strength of the depolarizing stimulus. This pe- excitability.16,181
riod is known as the absolute refractory period. The The relative refractory period results from in-
axon then enters a period of relative refractoriness activation of nodal transient Na⫹ channels. It is
that can be measured either as the increase in cur- prolonged by membrane depolarization and re-
rent required to produce a potential of a specified duced by hyperpolarization. Refractoriness may
size, known as refractoriness, or as the duration of therefore be used a measure of membrane poten-
the relative refractory period until threshold has tial, although it is essential to take into account
returned to baseline, usually 3– 4 ms. the effect of temperature, given that cooling leads
This period of refractoriness is followed by a to an increase in refractoriness.94 Furthermore,
period of superexcitability (or supernormality), dur- measures of refractoriness may be unreliable in
ing which there is a reduction in threshold occurring situations of impaired distal transmission, as may
over a 10 –15-ms interval. Finally, there is a late phase occur with axonal demyelination, neuromuscular
of raised threshold known as late subexcitability, junction abnormalities, muscle disease, or any
ending around 100 ms. These changes in threshold other factor that reduces the security of impulse
the neurotoxicity of this agent may be mediated by is unchanged. It may therefore be used to differen-
blockage of nodal transient Na⫹ channels.110 tiate between pure depolarization and depolariza-
Superexcitability is due to a depolarizing afterpo- tion secondary to nerve ischemia in which there is no
tential that results from the capacitative charging of significant change in late subexcitability due to com-
the internode by the action potential12 and subse- pensatory changes in extracellular K⫹ ions.92
quently discharges through high resistance pathways
under or through the myelin sheath.40,99 Recent NERVE EXCITABILITY STUDIES IN ESKD
studies have also suggested that activation of nodal
Na⫹ conductances may be a further contributing Nerve excitability studies in ESKD patients (Fig. 4)
factor.133 As for refractoriness, superexcitability also have recently demonstrated significant alterations in
varies with membrane potential, with depolarization membrane potential prior to hemodialysis, with re-
leading to a reduction in superexcitability and hy- covery in the postdialysis period.97,113,115–117 Prior to
perpolarization causing an increase. Late subexcit- dialysis, measures of nerve excitability were signifi-
ability is determined by activation of nodal slow K⫹ cantly abnormal in ESKD patients compared to con-
channels and the difference between membrane po- trol data.93,95,108 Stimulus–response curves were
tential (Er) and the K⫹ equilibrium potential (Ek) shifted to the right, indicating that axons were of
and increases with depolarization if extracellular K⫹ high threshold. This was accompanied by a fan-
CONCLUSION