Continuing Education Activity
Uremic encephalopathy is a cerebral dysfunction caused by the accumulation of toxins as a result of acute or chronic renal failure. The clinical presentation is broad, and the clinical course is always progressive when untreated. This activity describes the evaluation and treatment of uremic encephalopathy and highlights the role of the interprofessional team in the care of patients with this condition.
- Identify the etiology of uremic encephalopathy.
- Review the appropriate evaluation process for uremic encephalopathy.
- Outline the management options available for uremic encephalopathy.
- Summarize the importance of collaboration amongst the interprofessional team to optimize health care delivery to patients with uremic encephalopathy.
Uremic encephalopathy (UE) is defined as cerebral dysfunction due to the accumulation of toxins resulting from acute or chronic renal failure. The clinical presentation of UE is broad, varying from subtle to florid. The clinical course of UE is always progressive when untreated. UE is at least partially reversible with the initiation of renal replacement therapy. Therefore, UE is an indication to start renal replacement therapy.
Many compounds have been implicated in the pathogenesis of UE, and they are known as uremic toxins (UT). Urea is the most studied UT. While severe cognitive changes of uremic encephalopathy develop when the estimated glomerular filtration rate (eGFR) falls below 15mL/min, frequently cognitive changes can be identified at eGFR in the range of 40-60 mL/min. There is no threshold eGFR required to diagnose UE. Occasionally, a therapeutic trial with a hemodialysis session may be needed to make a diagnosis in retrospect.
Cognitive dysfunction can occur in up to 60% of patients with chronic kidney disease (CKD). Cognitive dysfunction is multifactorial and may be due to vascular injury, endothelial inflammation, or direct effects of the neurotoxins. The cause and effect of relationships between neurotoxins and cognitive dysfunction are uncertain. Therefore, it is difficult to estimate the prevalence of uremic encephalopathy.
Uremic encephalopathy increases morbidity and mortality of CKD patients. Uremic encephalopathy is an absolute indication to start renal replacement therapy. Hence, early diagnosis of UE is essential. Uremic encephalopathy is a clinical syndrome with a variable and subtle presentation. There is no confirmatory test, which leads to a delay in diagnosis. During the evaluation, it is essential to exclude conditions that may mimic UE, such as infection, osmotic demyelination, subdural hematomas, hypertensive encephalopathy, cerebrovascular accidents, disequilibrium syndrome, amongst others.
A proposed mechanism of UE is an accumulation of neurotoxins. Over 130 chemicals have been identified as potential neurotoxins. Examples are urea, indoxyl sulfate, guanidine compounds, indolic acid, phenols, and carnitine. Lanthionine, a derivative of sulfur-containing amino acids, is more recently recognized as a uremic toxin. The roles of these individual compounds in producing the clinical picture of uremic encephalopathy is unclear. More basic science research is needed to untangle the functions of these chemicals in causing uremic encephalopathy. The European Uremic Toxins (EUTox) workgroup is an international consortium of academic and medical researchers who are striving to understand the role of these compounds. These chemicals belong to diverse and unrelated groups such as peptides, ions, products of lipids, and carbohydrate metabolism. There is no ideal classification of the uremic toxins. Based on their physicochemical properties, uremic toxins may be classified as water-soluble, protein-bound, and middle molecules.
No common pathway has been identified, but overall, three processes may be contributing. These include an imbalance in the inhibitory and excitatory neurotransmitters, neuronal degeneration, and vascular inflammation.
According to one hypothesis, plasma and cerebrospinal fluid levels of glycine increase and glutamine and gamma-aminobutyric acid (GABA) decrease. The accumulation of guanidino compounds (the result of L-arginine metabolism) leads to the activation of excitatory N-methyl-D-aspartate (NMDA) receptors and further inhibition of inhibitory GABA receptors. Another mechanism proposed is hyperparathyroidism, which increases the calcium content in the brain cells. However, encephalopathy improves with dialysis, and this one does not have substantial effects on parathyroid hormone levels.
Recently a link between vascular endothelial dysfunction and cognitive dysfunction has been recognized and may be contributing to the clinical syndrome of UE.
The blood pressure regulatory neurons are located in the rostral ventrolateral medulla (RVLM). The RVLM contains the pre-sympathetic neurons. When exposed to high uric acid concentrations, indoxyl sulfate, and methyl guanidine, RVLM neuronal activity increases. Subsequent use of an antioxidant drug results in cessation of the RVLM activity, which suggests that the reactive oxidant species have a central role in the development of the clinical syndrome of UE. While urea is the surrogate for neurotoxins, which is lowered with dialysis, there is no credible evidence linking urea to encephalopathy. Recent studies have shown that indoxyl sulfate can cause vascular inflammation and neurological symptoms. The common mechanism appears to be oxidative stress.
Oxidative stress can alter the mitochondrial function. Dysfunctional mitochondria produce more uremic toxins developing into a self-perpetuating cycle. Metabolism of purine and urea cycle requires enzymes that are located within the mitochondria. Hence in patients with UE, there is an acquired mitochondrial defect. As a result, the uremic brains are not equipped to utilize the ATP requiring pathways compared to the normal healthy brains. Reactive oxygen species accumulation as a result of mitochondrial dysfunction and further aggravates oxidative stress. Reactive oxygen species due to oxidative stress result in endothelial dysfunction, myelin injury, and nitration of brain proteins leading to more uremic toxin production.
History and Physical
Uremic encephalopathy is a clinical syndrome with no established diagnostic criteria. The clinical presentation is variable and is determined by the rate of progression of the underlying kidney disease. In patients with a slow decline in eGFR, fatigue, anorexia, weight-loss, and nausea are the presenting signs. Cognitive dysfunction is slow, progressive, and subtle. Psychometric testing is required to identify the involvement of the central nervous system. At the other end of the spectrum are patients with a rapid decline in eGFR. These patients can present with confusion, delirium, seizures, and coma.
A physical exam reveals cognitive dysfunction in the form of abnormalities in memory, judgment, and ability to perform calculations. Hyperreflexia, asterixis, papilledema, and nystagmus are frequently present. Neuropathy and myopathy may be present.
There is no specific confirmatory test to diagnose UE. The workup should be rapid and geared towards excluding other conditions that mimic UE and are ubiquitous in patients with advanced-stage chronic kidney disease (CKD). Laboratory studies such as complete blood count (CBC), comprehensive metabolic panel (CMP), magnesium level, phosphorus level, lactic acid level, and toxicology screen should be ordered. Lumbar puncture is not helpful for the diagnosis of UE.
The electroencephalogram (EEG) is non-diagnostic. Often an EEG is performed in patients to exclude underlying seizures. EEG findings in UE include a loss of alpha frequency waves and slowing overall all, and intermittent bursts of theta and delta waves with slow background activity. These findings are non-specific. EEG waves slowing is directly proportional to the worsening renal function. After initiation of dialysis, the EEG changes stabilize but may not come back to baseline. Some improvement may occur over several months.
Cognitive tests that can be employed are the trail-making test, which measures psychomotor speed, the short term memory test, and the choice reaction time test, which measures simple decision making.
A computed tomography (CT) scan of the brain can exclude focal lesions. Magnetic resonance imaging (MRI) studies in uremic patients show widespread involvement of the brain. Abnormalities are found in the cortex, subcortical white matter, basal ganglia, and hippocampus. Such extensive lesions result in a variable clinical presentation. Based on MRI findings, patients with UE may be grouped into three types: 1. Cortical and subcortical involvement. Reversible posterior leukoencephalopathy syndrome (PRES) may also be present at the same time, 2. Bilateral basal ganglia involvement is seen in diabetic patients, and 3. White matter involvement only, which is rare. The presence of PRES in imaging studies performed for UE suggests a close relationship between vascular dysfunction and neuronal dysfunction, as described in the pathogenesis of UE. A published case demonstrated that the MRI changes of increased signal intensity are reversible after several intermittent hemodialyses (IHD) compared to continuous ambulatory peritoneal dialysis (CAPD). MRI changes involve multiple brain areas, and currently, there is no evidence to delineate the reversible and non-reversible changes in functional imaging. In general, dialysis must be adequate.
Treatment / Management
UE is an absolute indication to initiate renal replacement therapy (RRT). Sometimes, a therapeutic trial with RRT is needed in the setting of uremia. Management of CKD should be implemented simultaneously, such as the use of erythropoiesis-stimulating agents, phosphate binders, calcium replacement, and nutrition modification.
There is clinical evidence that intermittent hemodialysis (HD) is more effective than continuous ambulatory peritoneal dialysis (CAPD). However, there is a danger to precipitating dialysis disequilibrium syndrome (DDS) due to the risk of rapid osmotic changes at the start of HD. Mannitol is used to prevent DDS in the first few HD sessions. Twenty-five grams of mannitol can be given before starting hemodialysis for the first three sessions.
Studies have shown that the measured blood osmolality change is reduced by 60% with mannitol (10 mmol/kg fall in plasma osmolality was decreased to 4.3 mmol/kg with intravenous mannitol before HD). The symptoms of DDS were mild in the mannitol group and occurred in 10% of patients compared to 67% in the non-mannitol group despite similar ultrafiltration rates.
UE is a diagnosis of exclusion. The following should be considered in the differential diagnosis:
- Wernicke-Korsakoff’s encephalopathy
- Hypertensive encephalopathy
- Hyperosmolar coma
- Disequilibrium syndrome
- Metabolic encephalopathy
- Fluid and Electrolyte disturbances, such as hyponatremia and hypermagnesemia,
- Drug toxicity
- Posterior reversible encephalopathy syndrome
- Osmotic demyelination syndrome
- Hepatic encephalopathy
A mnemonic to remember a set of conditions that lead to diffuse cortical injury on MRI is “CRUMPLED.” This pneumonic stands for C for Creutzfeldt-Jakob disease, R for reversible cerebral vasoconstriction syndrome, U for uremic encephalopathy, M for mitochondrial cytopathy/encephalopathy, P for prolonged seizure/posterior reversible encephalopathy, L for laminar necrosis hypoxic-ischemic injury, L for liver disease, E for encephalitis (infectious), and D for diabetes mellitus- hypoglycemia.
With the initiation of RRT, the clinical syndrome of UE improves. This process may occur in days to weeks. The EEG changes take several months to recover and may not return to baseline. Some cognitive changes in the brain may be irreversible. That is one more reason to initiate RRT before the onset of UE.
Some of the complications of UE are seizures, coma, and death. Upon initiation of renal replacement therapy, UE may be partially reversed. However, some cognitive changes may become permanent.
Deterrence and Patient Education
Patients with advanced-stage CKD must be followed closely by nephrologists in the outpatient setting. The eGFR should be monitored at regular intervals, so dialysis can be initiated before UE develops.
Enhancing Healthcare Team Outcomes
Uremic Encephalopathy is a clinical syndrome with no established diagnostic criteria. These patients may exhibit non-specific signs and symptoms such as fatigue, anorexia, nausea, and confusion. The clinical presentation is variable, and one would have to consider another diagnosis, such as hypertensive encephalopathy, hyperosmolar coma, metabolic encephalopathy, and drug toxicity.
While the nephrologist is almost always involved in the care of patients with uremic encephalopathy, it is essential to consult with an interprofessional team of specialists, including neurologists, radiologists, neuropathologists, vascular neurologists, and urologists. The nurses are also vital members of the interprofessional group. They assist with clinical monitoring of patients and help with initiating hemodialysis, evaluating fistula, looking for signs of complications after procedures, and providing the education necessary for the patients and families. In hemodialysis treatment, pharmacists are key members in patient care, preventing medication-related problems and enhancing safe, effective medication use. The radiologists also have an important role in determining the cause, evaluating the abnormalities discovered in MRI or CT scans, and helping to correlate the clinical and imaging findings and exclude other diagnoses. Interprofessional teamwork is vital for early identification of uremic encephalopathy and prompt RRT initiation to prevent complications and mortality.