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Drugs & Diseases > Nephrology

Uremic Encephalopathy
Updated: May 02, 2017
 Author: James W Lohr, MD; Chief Editor: Vecihi Batuman, MD, FASN more...
Practice Essentials

Uremic encephalopathy is an organic brain disorder. It develops in patients

with acute or chronic renal failure, usually when the estimated glomerular
filtration rate (eGFR) falls and remains below 15 mL/min. [1, 2, 3, 4]
Manifestations of this syndrome vary from mild symptoms (eg, lassitude,
fatigue) to severe signs (eg, seizures, coma). Severity and progression
depend on the rate of decline in renal function; thus, symptoms are usually
worse in patients with acute kidney injury. Prompt identification of uremia as
the cause of encephalopathy is essential because symptoms are readily
reversible following initiation of dialysis. [5, 6]
Pathophysiology
Uremic encephalopathy has a complex pathophysiology, and many toxins that
accumulate in kidney failure may be contributive. Uremic encephalopathy may
occur in a patient with acute kidney injury or chronic kidney failure of any
etiology.
One contributing factor to uremic encephalopathy may involve imbalances of
neurotransmitter amino acids within the brain. During the early phase of
uremic encephalopathy, plasma and cerebrospinal fluid (CSF) determinations
indicate that levels of glycine increase and levels of glutamine and gamma-
aminobutyric acid (GABA) decrease. As uremia progresses, it has been
proposed that the accumulation of guanidino compounds results in activation
of excitatory N-methyl-D-aspartate (NMDA) receptors and inhibition of
inhibitory GABA receptors, which may cause myoclonus and seizures. [5, 7, 8] In
addition, alterations occur in metabolism of dopamine and serotonin in the
brain, which may lead to early symptoms (eg, sensorial clouding).
Parathyroid hormone (PTH) likely contributes to uremic
encephalopathy. [9] Secondary hyperparathyroidism, which occurs in kidney
failure, causes an increase in calcium content in the cerebral cortex. In animal
models with uremia, electroencephalographic (EEG) changes were typical of
those observed in patients with renal failure. In uremicpatients with secondary
hyperparathyroidism, EEG changes have been shown to improve after
medical suppression of PTH or parathyroidectomy.
The specific mechanism by which PTH causes disturbance in brain function is
unclear, but it may involve increases in intracellular concentration of calcium
in brain cells. However, since the encephalopathy improves with dialysis,
which does not have a marked effect on PTH levels, hyperparathyroidism is
not thought to be the main cause.
A study of acute kidney injury in mice found evidence of a blood-brain barrier
disruption from such injury, with increased neuronal pyknosis and
microgliosis. In addition, proinflammatory chemokines were increased in brain
tissue. [10]
Numerous other uremic toxins may contribute to uremic encephalopathy, but
there has been a notable lack of research in this area. Although the
encephalopathy correlates roughly with blood urea nitrogen (BUN) level, urea
is not itself thought to be causative.
Epidemiology
Frequency
United States
Most patients with an eGFR of less than 10 mL/min develop some degree of
encephalopathy; however, they may not be clearly symptomatic. In one
pediatric study, encephalopathy occurred in 40% of the children with a BUN
level greater than 90 mg/dL. As the BUN level increased, the likelihood of
these children developing convulsions increased. [11]
Mortality/Morbidity
Symptoms include somnolence and decreased mentation. Asterixis may
be present. These findings are reversible following initiation of dialysis and
recovery of renal function in patients with acute kidney injury. Symptoms are
also reversible following the institution of dialysis or renal transplantation in
patients with end-stage renal disease (ESRD). The severe complications (ie,
seizures, coma) can lead to death. Early recognition of encephalopathy in the
setting of decreased renal function is crucial to prevent morbidity or mortality.
With prompt dialytic therapy, the mortality rate is low.
Race-, Sex-, and Age-related Demographics
No racial predilection exists. No significant association between sex and
incidence exists. Uremic encephalopathy may develop at any age.

. History
Early symptoms of uremic encephalopathy include the following:
 Anorexia
 Nausea
 Restlessness
 Drowsiness
 Diminished ability to concentrate
 Slowed cognitive functions
More severe signs and symptoms of uremic encephalopathy include the
following:
 Vomiting
 Emotional volatility
 Decreased cognitive function
 Disorientation
 Confusion
 Bizarre behavior
 Stupor, coma
Physical
Physical examination findings may include the following:
 Altered mental status (confusion)
 Cranial nerve signs (nystagmus)
 Papilledema
 Hyperreflexia, clonus, asterixis
 Altered gait
 Stupor
 Coma (occurs only if uremia remains untreated and progresses

Laboratory Studies
Obtain the following laboratory studies:
 Renal function studies [12] – Markedly elevated blood urea nitrogen (BUN)
and creatinine levels are seen in uremic encephalopathy
  Serum electrolyte and glucose measurements – To rule
out hyponatremia, hypernatremia, hyperglycemia, and hyperosmolar
syndromes as the cause of encephalopathy
 Complete blood cell count – To detect leukocytosis, which may suggest an
infectious cause, and to determine whether anemia is present (anemia may
contribute to the severity of mental alterations)
 Serum calcium, phosphate, and parathyroid hormone (PTH) levels – To
assess for hypercalcemia, hypophosphatemia, and
severe hyperparathyroidism, which cause metabolic encephalopathy
 Serum magnesium level – This may be elevated in a patient with renal
insufficiency, particularly if the patient is ingesting magnesium-containing
antacids; hypermagnesemia may manifest as encephalopathy
 Toxicology screen
 Medication levels
Determine drug levels because medications (eg, digoxin, lithium) may
accumulate in patients with kidney failure and contribute to encephalopathy.
However, some medications that are excreted by the kidney cannot be detected.
These may also accumulate in patients with kidney failure, resulting in
encephalopathy (eg, penicillin, cimetidine, meperidine, baclofen).
Imaging Studies
Obtain a magnetic resonance imaging (MRI) or computed tomography (CT) scan
of the head for a uremic patient who presents with severe neurologic symptoms,
to rule out structural abnormalities (eg, cerebrovascular accident, intracranial
mass, subdural hematoma).
Typical MRI findings in patients with uremic encephalopathy include increased
signal intensity (lentiform fork sign) in either the cerebral cortex or the basal
ganglia. [13, 14] A CT scan may show bilateral hypodensities involving the basal
ganglia, midbrain, or thalamus.[15]

Encephalography
An electroencephalograpm (EEG) is commonly performed on patients with
metabolic encephalopathy. Findings typically include the following:
 Slowing and loss of alpha frequency waves
 Disorganization
 Intermittent bursts of theta and delta waves with slow background activity

Approach Considerations (treatment)

The presence of uremic encephalopathy in a patient with either acute kidney
injury or chronic kidney failure is an indication for the initiation of dialytic
therapy (ie, hemodialysis, peritoneal dialysis, continuous renal replacement
therapy). After beginning dialysis, the patient generally improves clinically,
although electroencephalographic (EEG) findings may not improve immediately.
In patients with end-stage renal disease (ESRD), EEG abnormalities generally
improve after several months but may not completely normalize.
Address the following factors when treating uremic encephalopathy, which are
also included in the standard care of any patient with ESRD:
 Adequacy of dialysis
 Correction of anemia
 Regulation of calcium and phosphate metabolism
Consultations
See the list below:
 Consult a neurologist if symptoms do not improve upon initiation of dialysis
therapy.
 Consult a vascular surgeon for placement of vascular access in patients with
ESRD.
 Refer patients with ESRD to a dietitian familiar with renal diseases.
Diet
To avoid malnutrition in patients with ESRD, maintain adequate protein intake
(1.2 g/kg/d) and initiate dialysis (despite the presence of encephalopathy

Lohr, James W. Neurological Manifestations of Uremic Encephalopathy. May 2, 2017. (Cited

September 20, 2018) Available from: http://emedicine.medscape.com/article/ 1135651-
overview#showall.

Patofisiologi

Ensefalopati uremik memiliki patofisiologi yang kompleks, dan banyak toksin yang terakumulasi pada
gagal ginjal dapat berkontribusi. Encephalopathy uremik dapat terjadi pada pasien dengan cedera ginjal
akut atau gagal ginjal kronis etiologi apa pun.

Salah satu faktor yang berkontribusi terhadap ensefalopati uremik dapat melibatkan ketidakseimbangan
asam amino neurotransmitter di dalam otak. Selama fase awal ensefalopati uremik, plasma dan cairan
serebrospinal (CSF) menentukan bahwa kadar glisin meningkat dan kadar glutamin dan asam gamma-
aminobutyric (GABA) menurun. Ketika uremia berkembang, telah diusulkan bahwa akumulasi senyawa
guanidino menghasilkan aktivasi reseptor N-methyl-D-aspartat (NMDA) rangsang dan penghambatan
reseptor GABA penghambatan, yang dapat menyebabkan mioklonus dan kejang. [5, 7, 8] Selain itu,
perubahan terjadi pada metabolisme dopamin dan serotonin di otak, yang dapat menyebabkan gejala
awal (misalnya, pengaburan sensorik).

Hormon paratiroid (PTH) kemungkinan berkontribusi pada ensefalopati uremik. [9] Hiperparatiroidisme
sekunder, yang terjadi pada gagal ginjal, menyebabkan peningkatan kandungan kalsium dalam korteks
serebri. Pada model binatang dengan uremia, perubahan electroencephalographic (EEG) adalah khas
dari yang diamati pada pasien dengan gagal ginjal. Pada pasien uremik dengan hiperparatiroidisme
sekunder, perubahan EEG telah terbukti membaik setelah penekanan medis PTH atau paratiroidektomi.
Mekanisme spesifik yang menyebabkan PTH menyebabkan gangguan fungsi otak tidak jelas, tetapi
mungkin melibatkan peningkatan konsentrasi kalsium intraseluler dalam sel-sel otak. Namun, karena
ensefalopati meningkat dengan dialisis, yang tidak memiliki efek yang nyata pada tingkat PTH,
hiperparatiroidisme tidak dianggap sebagai penyebab utama.

Sebuah penelitian cedera ginjal akut pada tikus menemukan bukti gangguan penghalang darah-otak dari
cedera tersebut, dengan peningkatan neuronal pyknosis dan microgliosis. Selain itu, kemokin
proinflamasi meningkat di jaringan otak. [10]

Banyak racun uremik lainnya dapat berkontribusi pada ensefalopati uremik, tetapi ada kurangnya
penelitian di bidang ini. Meskipun ensefalopati berkorelasi kasar dengan tingkat nitrogen urea darah
(BUN), urea sendiri tidak dianggap sebagai penyebab.