Uremic Encephalopathy and Other Brain

Disorders Associated with Renal Failure

Julian Lawrence Seifter, M.D.,1 and Martin A. Samuels, M.D.2

ABSTRACT

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Kidney failure is one of the leading causes of disability and death and one of the
most disabling features of kidney failure and dialysis is encephalopathy. This is probably
caused by the accumulation of uremic toxins. Other important causes are related to the
underlying disorders that cause kidney failure, particularly hypertension. The clinical
manifestations of uremic encephalopathy include mild confusional states to deep coma,
often with associated movement disorders, such as asterixis. Most nephrologists consider
cognitive impairment to be a major indication for the initiation of renal replacement
therapy with dialysis with or without subsequent transplantation. Sleep disorders,
including Ekbom’s syndrome (restless legs syndrome) are also common in patients
with kidney failure. Renal replacement therapies are also associated with particular
neurologic complications including acute dialysis encephalopathy and chronic dialysis
encephalopathy, formerly known as dialysis dementia. The treatments and prevention of
each are discussed.

KEYWORDS: Uremic encephalopathy, uremia, restless legs syndrome, dialysis

dementia, dialysis encephalopathy

T he syndrome of uremic encephalopathy produ-
ces a spectrum of brain abnormalities that range from
mild inattention to coma. In addition, patients with
renal failure are subject to other related encephalopa-
thies, including various sleep disorders, the neurologic
consequences of malnutrition, and the complications of
renal replacement therapy.
PATHOGENESIS
In patients with uremia, the brain shows decreased
metabolic activity and oxygen consumption.1,2 As long
as the cause of the underlying renal disease (e.g., hyper-
tension) has not affected cerebral hemodynamics and
responsiveness to carbon dioxide, these functions appear
intact, but subtle disturbances have been detected fol-
lowing dialysis.
Most data suggest a role of uremic toxins that
accumulate due to renal failure. The balance of excitatory
and inhibitory neurotransmitters may be disrupted by
organic substances,3 in particular guanidino compounds,
which are increased in the cerebrospinal fluid.4,5 These
compounds antagonize g-aminobutyric acid (GABAA)
receptors and at the same time have agonistic effects on
N-methyl-D-aspartate glutamate receptors, leading to
enhanced cortical excitability. Asymmetrical dimethyl
arginine,6 which is increased in patients with renal fail-
ure, inhibits endothelial nitric oxide synthase and levels

1
Department of Nephrology, 2Department of Neurology, Brigham and
Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Address for correspondence and reprint requests: Martin A.
Samuels, M.D., Chairman, Department of Neurology, Brigham and
Women’s Hospital, Professor of Neurology, Harvard Medical School,
75 Francis Street, Boston, MA 02115 (e-mail: msamuels@partners.
org).
Acute and Subacute Encephalopathies; Guest Editor, Martin A.
Samuels, M.D.
Semin Neurol 2011;31:139–143. Copyright # 2011 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1277984.
ISSN 0271-8235.
139
140 SEMINARS IN NEUROLOGY/VOLUME 31, NUMBER 2 2011
correlate with cerebrovascular complications in uremia.
Disturbances in monoamine metabolism include a
depletion of norepinephrine, and suppression of central
dopamine, which has been linked to the impairment of
motor activity in uremic rats. Myoinositol, carnitine,
indoxyl sulfate, polyamines, and decreased transport
functions and increased permeability of the central
nervous system (CNS) have also been implicated in
the neuronal dysfunction of uremia. Metabolites of
drugs, including cimetidine and acyclovir, may be in-
creased in uremia due to inhibition of the organic anion
transporter (OAT-3) and neurotoxic syndromes may
result.7 Levels of opiates, and in particular metabolites
of meperidine, increase in plasma due to decreased
excretion through cation secretory transport with sub-
sequent neurotoxicity.
Secondary hyperparathyroidism may also play a
role in uremic encephalopathy,8,9 as brain calcium is
increased in renal failure and calcium transporters within
neurons are parathyroid hormone sensitive. Increased
cellular calcium may play a role in neuroexcitation.
Appetite regulation is abnormal in uremia. A high
rate of tryptophan entry across the blood–brain barrier
may increase the synthesis of serotonin, a major appetite
inhibitor.10 High levels of cholecystokinin, a powerful
anorectic, and low levels of neuropeptide Y, an appetite
stimulant, have been observed. Cachexia may result from
anorexia, acidosis, and inflammation. Inflammatory cy-
tokines such as leptin, tumor necrosis factor a, and
interleukin-1 may signal anorexigenic neuropeptides
such as pro-opiomelanocortin and a-melanocyte–stim-
ulating hormone in the arcuate nucleus of the hypothal-
amus. All of these factors converge to create a state of
malnutrition in many patients with renal failure.
CLINICAL MANIFESTATIONS
Whereas 20% of patients with acute kidney injury in an
intensive care unit setting developed neurologic impair-
ment,11 in chronic renal failure the syndrome is more
subtle, not correlating closely to the severity of the
uremia.1,12 Population studies in hemodialysis patients
found cognitive impairment in 30% with 10% exhibit-
ing severe impairment. Neurocognitive deficits may have
special implications for chronic kidney disease in early
childhood, adversely affecting development of the
brain.13
Uremic encephalopathy can manifest as complex
mental changes and/or motor disturbances. The full-
blown syndrome is a risk factor for morbidity and
mortality.1,2 Mental changes include emotional changes,
depression, disturbing and disabling cognitive and mem-
ory deficits, and in the most severe form, a generalized
disorder characterized by confusion, delirium (i.e., agi-
tated confusion), psychosis, seizures, coma, and ulti-
mately death. Such advanced uremic encephalopathy is
usually only seen in patients in whom a decision has been
made not to initiate renal replacement therapy. Severe
motor symptoms or signs are rare. Depression and
anxiety, including suicidal thoughts, are important
underdiagnosed and undertreated aspects of uremia
and may be related to endogenous toxins, poor nutri-
tional state, fear of dialysis, or death. Other known
causes of depression should always be sought.
Stable uremic encephalopathy is manifested by
fine action tremor, asterixis, and hyperreflexia. Asterixis
is characterized by intermittent loss of muscular tone in
antigravity muscles. It is distinguished from tremor by
the fact that it is not an oscillation but rather intermit-
tent loss of tone. Myoclonus is also seen in patients with
uremic encephalopathy. It is similar in timing to asterixis
(10–100 ms), but is due to activation of antigravity
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muscles. For this reason, some consider asterixis to be
a form of negative myoclonus. The distinction between
asterixis and myoclonus is less important than once
thought, as both or either may be present in many
metabolic encephalopathies and some structural brain
diseases as well. Asterixis and myoclonus may be elicited
with the hands outstretched, but may be more sensitively
assessed by looking at the protruded tongue or the index
finger raised with the palm placed on a firm surface.
Asterixis and myoclonus may be seen in patients with
renal impairment who have received various drugs (e.g.,
metoclopramide, phenothiazines, antiepileptic drugs in-
cluding gabapentin, and opioids, especially meperidine).
Metabolic acidosis may also produce an indistinguish-
able encephalopathy as can aluminum toxicity. There-
fore, before concluding encephalopathy to be a clinical
feature of advanced uremia requiring renal replacement
therapy, a careful search for other causes should be
initiated.
Advanced uremic encephalopathy is usually char-
acterized by a reduced level of consciousness, anorexia,
asterixis and/ myoclonus, and upper motor neuron signs
that result in disturbances of gait and speech.
DIAGNOSIS AND DIFFERENTIAL
DIAGNOSIS
The diagnosis of uremic encephalopathy is based on
clinical findings and their improvement after adequate
therapy (see next section). Lumbar puncture, electro-
encephalogram (EEG), and imaging procedures largely
serve to exclude other etiologies in patients in whom the
clinical diagnosis is doubtful. In uremic encephalopathy,
the cerebrospinal fluid is often abnormal, sometimes
demonstrating a modest pleocytosis (usually < 25 cells/
mm3) and increased protein concentration (usually
< 100 mg/dL). The EEG is usually abnormal, but
nonspecific. Generalized slowing with an excess of delta
and theta waves is found.14 Brain imaging usually shows
cerebral atrophy and enlargement of the ventricles.
 UREMIC ENCEPHALOPATHY AND OTHER BRAIN DISORDERS ASSOCIATED WITH RENAL FAILURE/SEIFTER, SAMUELS
The differential diagnosis of uremic encephalop-
athy includes hypertensive encephalopathy (posterior
reversible encephalopathy syndrome), systemic inflam-
matory response syndrome observed in septic patients,
systemic vasculitis, drug-induced neurotoxicity (e.g.,
opioids, benzodiazepines, neuroleptics, antidepressants),
cerebral vascular disease (small and large vessel), sub-
dural hematoma. Seizure activity may be secondary to
uremic encephalopathy, hypertensive encephalopathy,
cerebral embolism, cerebral venous thrombosis, or elec-
trolyte and acid-base abnormalities. Tetany can develop
when treatment involves alkalinization of an acidemic
patient with renal disease and hypocalcemia.
TREATMENT
Most nephrologists consider advanced cognitive or
memory impairment an indication for initiation of renal
replacement therapy. Most of the manifestations of CNS
involvement are reversible with dialysis within days or
weeks, but mild signs of uremic encephalopathy may
persist. In dialyzed patients with persistent or recurrent
symptoms, increasing the delivered dialysis dose may
improve clinical findings. Successful renal transplanta-
tion usually results in resolution of the uremic encephal-
opathy syndrome within days.
Correction of anemia with recombinant erythro-
poietin in the dialysis patient to a target hemoglobin of
11 to 12 g/dL may be associated with improved cognitive
function and decreased slowing on the EEG.15 Too
rapid overcorrection of anemia may be associated with
seizures. Similarly, parathyroid hormone (PTH) sup-
pression with vitamin D analogues and cinacalcet is
important given the potential role of PTH as a neuro-
toxin. Treatment of psychosis in kidney disease must
take into account the pharmacokinetics of the specific
agent. For example, resperidone may have utility, but
dose reduction is necessary due to a prolonged half-life
in patients with renal failure.
SLEEP DISORDERS
Many hemodialysis and peritoneal dialysis patients ex-
hibit obstructive sleep apnea that is independent of
obesity.16 The associated sleep deprivation contributes
to fatigue and cognitive impairment, and increases the
risk of cardiovascular complications.16 Both obstructive
and central sleep apnea are seen in patients with renal
failure. Treatment of obstructive sleep apnea, using
continuous positive airway pressure in a fashion similar
to the treatment of nonuremic individuals is effective.
Nocturnal hemodialysis significantly reduces the occur-
rence of sleep apnea.16
Daytime sleepiness is common and underdiag-
nosed in patients with renal failure and contributes not
only to worsened hypertension and increased cardiovas-
141
cular risk but also to social dysfunction. Whether ob-
structive sleep apnea and its associated excessive daytime
sleepiness is an independent risk factor for the progres-
sion of renal failure is not yet settled. Sleep deprivation
may be assessed with a multiple sleep latency test. If the
duration of time from ‘‘lights out’’ to the onset of sleep is
less than 5 minutes, this suggests sleep deprivation in
this clinical context. There is also a reduced proportion
of rapid eye movement sleep. Increased arousal fre-
quency is probably multifactorial, including the existence
of periodic limb movements during sleep, pain, pruritus,
neuropathic pain, and sleep apnea.
RESTLESS LEG SYNDROME (EKBOM’S
SYNDROME)
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Restless leg syndrome (RLS), described by K.A. Ekbom
in 1944,17 is frequent in patients with renal failure,
particularly in women. It may result from a decrease in
dopaminergic modulation of intracortical excitability,
with reduced supraspinal inhibition and increased spinal
cord excitability. Restless leg syndrome is characterized
by unpleasant ‘‘creeping’’ sensations in the extremities
and a compulsive need to move the limbs, usually the
legs.18–20 The movement is worsened by periods of rest
or inactivity and is relieved by walking or stretching.
Symptoms are worse at night and may lead to insomnia
and consequent daytime sleepiness and reduced quality
of life. Nocturnal muscle cramps are also common in
patients with renal failure and should be distinguished
from RLS. Ekbom’s syndrome consists of restless legs,
plus other obsessive compulsive-like disorders, including
various pica behaviors, such as pagophagia (ice eating),
geophagia (clay eating), and amylophagia (starch eating).
Periodic limb movements is a disorder character-
ized by episodes of involuntary repetitive extension of
the big toe and dorsiflexion of the ankle, as well as
flexion of the knee and hip.19,20 This disorder is more
likely to occur in those with RLS.
Iron deficiency and/or iron transport into the
CNS plays a central role in RLS. Iron is a cofactor for
the enzyme tyrosine hydroxylase, the rate-limiting step
in the biosynthesis of dopamine, possibly explaining the
link between iron deficiency and dopamine deficiency in
RLS. Overt iron deficiency is easily diagnosed and
should be treated.19,20 In patients with normal red blood
cell indices and serum iron and total iron binding
capacity, a serum ferritin should be tested. Transferrin
saturation ratio may be an even more sensitive indicator
of iron deficiency. If these are both normal, a spinal fluid
ferritin may reveal a subtle CNS iron-deficiency syn-
drome. Restless leg syndrome often persists after initia-
tion of dialysis, but may improve after transplantation
and has been linked to abnormalities in calcium and
phosphorus metabolism, as well as anemia. Iron replace-
ment should be initiated if there is any indication of iron
142 SEMINARS IN NEUROLOGY/VOLUME 31, NUMBER 2 2011
deficiency. Oral replacement is the safest method.
Though intravenous (IV) iron may be effective, this
has not been demonstrated in carefully controlled clinical
trials in this setting. Dopaminergic treatment is often
helpful, usually starting with the dopamine receptor
agonists, pramipexole and ropinirole. Levodopa com-
bined with decarboxylase inhibitors (e.g., Sinemet) may
be used as well as gabapentin, opioids, and benzodiaze-
pines.18–20 Care should be taken with gabapentin be-
cause of toxicity with accumulation, the symptoms of
which are sedation, cognitive slowing, and various move-
ment disorders, including tremor and asterixis. Older
dopamine receptor agonists, such as bromocriptine and
pergolide, are rarely used now for RLS.
ENCEPHALOPATHIES ASSOCIATED WITH
RENAL REPLACEMENT THERAPY
Renal replacement therapy is associated with an in-
creased incidence of subdural hematoma and intracranial
hemorrhage, presumably related to hypertension and
anticoagulation with hemodialysis, as well as Wernicke’s
encephalopathy.1,2 Wernicke’s encephalopathy (thi-
amine deficiency) may occur in any malnourished pa-
tient, including those with renal failure. The full clinical
triad of mental symptoms (e.g., confusion, amnesia),
ataxia, and ocular abnormalities (e.g., nystagmus, abdu-
cens paresis, ptosis) is rarely present, so it is common
practice to provide supplementary thiamine in all mal-
nourished patients, particularly those with any type of
encephalopathy. Measuring thiamine in the serum and
testing for red cell transketolase may be done, but as
thiamine is a benign vitamin, it is more practical to
simply provide adequate supplementation.
Dialysis dysequilibrium syndrome is a rare com-
plication of rapid metabolic changes occurring with
hemodialysis, usually affecting patients in whom hemo-
dialysis is being initiated.21 It is most common in those
patients with severe uremia of long duration and with
severe hypertension. Characterized by acute onset of
headache, nausea, vomiting, disorientation, a confusional
state, and seizures, it is a diagnosis of exclusion. It usually
results from acute changes in osmolality during hemo-
dialysis, where the rapid decrease in urea in the extrac-
ellular fluid favors water movement into brain cells,
resulting in cerebral edema. Alternatively, other intra-
cellular osmolytes within brain cells may draw water from
the extracellular fluid. The syndrome normally reverses
spontaneously after a period of regular hemodialysis. If no
improvement is seen after a month of hemodialysis, one
should investigate for other possible causes of the clinical
syndrome by imaging the brain, obtaining an EEG, and
examining the spinal fluid. Dialysis disequilibrium syn-
drome may be prevented by decreasing hemodialysis
length to 2 to 3 hours, dialyzing daily, and reducing
hemodialysis efficacy during the first sessions.
Dialysis encephalopathy (formerly called dialysis
dementia) is probably a multifactorial syndrome occur-
ring in sporadic-endemic and epidemic types. In partic-
ular, in the latter, aluminum-based phosphate binders
and exposure to a dialysate containing > 20 mg/L
aluminum are considered to be a major cause.22 Alumi-
num transferred to the nervous system by transferrin
results in a characteristic clinical condition with prom-
inent stuttering that usually worsens toward the end of a
dialysis session as well as encephalopathy. This initially
responds well to IV benzodiazepines, but then becomes
unresponsive leading to a severe encephalopathy and
death. With the almost universal preparation of dialysate
water by reverse osmosis and the marked reduction in
aluminum-containing phosphate binder use, aluminum-
induced encephalopathy has virtually disappeared. If
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present, aluminum toxicity is treated with deferoxamine.
Renal transplantation is an effective treatment of dialysis
dementia.
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