Uremic encephalopathy is an organic brain disorder. It develops in patients with acute kidney injury or chronic kidney disease, usually when the estimated glomerular filtration rate (eGFR) falls and remains below 15 mL/min.[1, 2, 3, 4, 5]
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 kidney 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.[1]
See also Neurological Manifestations of Uremic Encephalopathy.
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. Likely causes include the following[1] :
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. It has been proposed that as uremia progresses, 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.[6, 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 uremic patients 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.
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]
No racial predilection exists. No significant association between sex and incidence exists. Uremic encephalopathy may develop at any age.
Symptoms include somnolence and decreased mentation. Asterixis may be present. These findings are reversible following initiation of dialysis and recovery of kidney function in patients with acute kidney injury. Symptoms are also reversible following the institution of dialysis or kidney 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 kidney function is crucial to prevent morbidity or mortality. With prompt dialytic therapy, the mortality rate is low.
Early symptoms of uremic encephalopathy include the following:
More severe signs and symptoms of uremic encephalopathy include the following:
Physical examination findings may include the following:
Obtain the following laboratory studies:
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).
Obtain a magnetic resonance imaging (MRI) or computed tomography (CT) scan of the head in uremic patients who present with severe neurologic symptoms, to rule out structural abnormalities (eg, stroke, intracranial mass, subdural hematoma). A CT scan may show bilateral hypodensities involving the basal ganglia, midbrain, or thalamus.[13]
Typical MRI findings in patients with uremic encephalopathy include increased signal intensity in either the cerebral cortex or the basal ganglia. A characteristic indicator of uremic encephalopathy on MRI is the lentiform fork sign, which consists of bilateral symmetrical hyperintensities in the basal ganglia encircled by a hyperintese rim that delineates the lentiform nucleus.[13, 14]
In a prospective study of 20 patients diagnosed with uremic encephalopathy, MRI scans did not show basal ganglia findings, and the lentiform fork sign was not observed. However, in the majority of patients the MRI showed white matter involvement and cerebral or cortical atrophy, and in half the patients, arterial blood gas (ABG) analysis revealed metabolic acidosis. The researchers concluded that while the lentiform fork sign and basal ganglia involvement can confirm the diagnosis, uremic encephalopathy cannot be ruled out in its absence; in those cases, clinical manifestations and laboratory findings need to be taken into account.[15]
An electroencephalogram (EEG) is commonly performed on patients with metabolic encephalopathy. Findings typically include the following:
Reduction in frequency of EEG waves correlates with the decrease in kidney function and the alterations in cerebral function. After the initial period of dialysis, clinical stabilization may occur while the EEG findings do not improve. Eventually, EEG results move toward normal.
Aside from the routine EEG, evoked potentials (ie, EEG signals that occur at a reproducible time after the brain receives a sensory stimulus [eg, visual, auditory, somatosensory]) may be helpful in evaluating uremic encephalopathy. Chronic kidney failure prolongs latency of the cortical visual-evoked response. Auditory-evoked responses are generally not altered in uremia, but delays in the cortical potential of the somatosensory-evoked response do occur.
Several cognitive function tests are used to evaluate uremic encephalopathy, including the following:
Alterations in choice reaction time appear to correlate best with kidney failure.
Lumbar puncture is not routinely performed; however, it may be indicated to find other causes of encephalopathy if a patient's mental status does not improve after initiation of dialysis. No specific CSF finding indicates uremic encephalopathy.
Uremic encephalopathy in a patient with either acute kidney injury or chronic kidney disease is an indication for the initiation of dialytic therapy (ie, hemodialysis, peritoneal dialysis, continuous renal replacement therapy). Yanai et al reported three cases of uremic encephalopathy that developed in anuric patients receiving peritoneal dialysis; all cases resolved with institution of hemodialysis.[16]
After beginning dialysis, patients generally show clinical improvement, although electroencephalographic (EEG) findings may not improve immediately. In patients with end-stage kidney disease (ESKD), 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 ESKD:
Administer medications (eg, iron, erythropoietin, phosphate binders, vitamin D analogues) for patients with ESKD to optimize their quality of life. Sedatives should be avoided.
Consult a neurologist if symptoms do not improve upon initiation of dialysis. Consult a vascular surgeon for placement of vascular access in patients with ESKD. Refer patients with ESKD to a dietitian familiar with kidney disease. Refer patients with chronic kidney disease to a nephrologist for regular monitoring of estimated glomerular filtration rate (eGFR), so that dialysis may be initiated before encephalopathy develops.
Elevated protein catabolism and protein malnutrition can complicate chronic kidney disease (CKD) and ESKD, and so should have an individualized meal plan devised under the supervision of a nephrology dietitian. Patients who are not on dialysis can maintain a neutral or slightly positive nitrogen balance with a low-quantity (~0.6 g/kg/day) but high-quality protein diet and adequate energy intake. Patients who are on dialysis have much higher protein requirements (1.2–1.3 g/kg/day).[17]
Schedule maintenance hemodialysis for patients who have ESKD.
Mental status should be carefully monitored.