Continuing Education Activity

Uremic encephalopathy is a cerebral dysfunction caused by the accumulation of toxins resulting from acute or chronic renal failure. The clinical presentation is broad, and the clinical course is always progressive when untreated. The syndrome likely results from alterations in hormonal metabolism, retention of uremic solutes, changes in electrolyte and acid-base homeostasis, blood-brain barrier transport, changes in vascular reactivity, and inflammation. There are no diagnostic clinical, laboratory, or imaging findings, and often the diagnosis is made retrospectively when symptoms improve after dialysis or transplantation. If there is no improvement in symptoms after clearing toxic solutes, a search for other explanations should begin. 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.

Objectives:

• 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 among the interprofessional team to optimize health care delivery to patients with uremic encephalopathy.

Introduction

Uremic encephalopathy (UE) is defined as cerebral dysfunction due to the accumulation of toxins resulting from acute or chronic renal failure.[1][2][3] It usually develops in patients with acute or chronic renal failure when their estimated glomerular filtration rate (eGFR) decreases and stays below 15 mL/min.[3] The clinical presentation of uremic encephalopathy 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, uremic encephalopathy is an indication to start renal replacement therapy.[2]

The syndrome likely results from alterations in hormonal metabolism, retention of uremic solutes, changes in electrolyte and acid-base homeostasis, blood-brain barrier transport, changes in vascular reactivity, and inflammation. There are no diagnostic clinical, laboratory, or imaging findings, and often the diagnosis is made retrospectively when symptoms improve after dialysis or transplantation. If there is no improvement in symptoms after clearing toxic solutes, a search for other explanations should begin.[4]

Etiology

Causes of uremic encephalopathy generally include all the factors that can lead to the accumulation of uremic toxins in a patient, such as the causes of acute kidney injury and chronic kidney disease. Many compounds have been implicated in the pathogenesis of uremic encephalopathy, known as uremic toxins (UT). Urea is the most studied UT. While severe cognitive changes of uremic encephalopathy develop when eGFR falls below 15 mL/min, mild to moderate cognitive changes can be identified at eGFR in the range of 40 to 60 mL/min.[3][5]

Generally, uremic toxins build up in a patient's blood when they develop acute kidney injury, secondary to a number of reasons. They are either unable to get the solutes cleared up with the help of renal replacement therapy, or they fail to respond to therapy. The list of these causes is extensive, for example, drugs, toxins, prolonged hypotension, dehydration, sepsis, blood loss, etc.[6][7] Uremic encephalopathy can also develop in chronic kidney disease patients when their eGFR falls due to any acute insult, such as infection, drugs, excessive vomiting or diarrhea, etc. Patients on hemodialysis can also develop uremic encephalopathy when they receive inadequate hemodialysis for several reasons, such as noncompliance and arteriovenous fistula dysfunction.[8]

Epidemiology

The lack of evident defining characteristics of uremia makes data difficult to interpret. However, severe encephalopathy seems to be an uncommon phenomenon in patients with progressive CKD, as most patients will start renal replacement therapy before severe encephalopathy ensues. This may be an uncommon phenomenon in the setting of acute kidney injury, where the decline in GFR is less predictable and more rapid.[4]

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 the relationships between neurotoxins and cognitive dysfunction are uncertain. Therefore, it is difficult to estimate the prevalence of uremic encephalopathy. In one pediatric study, uremic encephalopathy was observed in 40% of the patients with a blood urea nitrogen (BUN) level of more than 90 mg/dL. As this level increased, the propensity of these children to develop convulsions increased.[9]

Uremic encephalopathy increases the morbidity and mortality of CKD patients.[1] Symptoms are reversible with the initiation of dialysis and clearance of toxic solutes in patients with acute kidney injury. The condition is also reversible with the institution of dialysis or kidney transplantation in end-stage renal disease (ESRD) patients. Severe complications, such as seizures and coma, can lead to death. Early recognition of neurological signs in the setting of impaired renal function is critical to prevent morbidity or mortality. The mortality rate can be lowered with prompt dialytic therapy.[10]

No racial predilection exists. There is no link between gender and the incidence of uremic encephalopathy. Uremic encephalopathy may occur at any age.

Pathophysiology

A proposed mechanism of uremic encephalopathy is an accumulation of neurotoxins.[3][5] Over 130 chemicals have been identified as potential neurotoxins.[11] 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.[12] The roles of these individual compounds in producing the clinical picture of uremic encephalopathy are 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 striving to understand these compounds' role. These chemicals belong to diverse and unrelated groups, such as peptides, ions, products of lipids, and carbohydrate metabolism. There is no ideal classification of 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 three processes may contribute overall. 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.[2][13][14] Another mechanism proposed is hyperparathyroidism, which increases the calcium content in the brain cells.[15] 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 antioxidant drugs results in cessation of the RVLM activity, which suggests that the reactive oxidant species have a central role in developing the clinical syndrome of UE. While urea is the surrogate for neurotoxins, which are 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.[16] The common mechanism appears to be oxidative stress.

Oxidative stress can alter mitochondrial function. Dysfunctional mitochondria produce more uremic toxins developing into a self-perpetuating cycle.[11] Metabolism of the 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 normal healthy brains. Reactive oxygen species accumulate due to mitochondrial dysfunction and further aggravate 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.[17]

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 signs. Cognitive dysfunction is slow, progressive, and subtle in such patients.[18] Symptoms may include restlessness, drowsiness, diminished ability to concentrate, and slowed cognitive functions. 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 more severe features of uremic encephalopathy, such as confusion, delirium, seizures, disorientation, emotional volatility, and coma.[19]

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. In addition, neuropathy and myopathy may be present.

Evaluation

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, and disequilibrium syndrome, among others.

Laboratory Evaluation

There is no specific confirmatory test to diagnose uremic encephalopathy. Renal function tests reveal markedly elevated BUN and creatinine levels in uremic encephalopathy.[20] 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). A complete blood count (CBC) should be done to see leucocytosis, which could indicate an underlying infection. One should also consider doing serum electrolyte and glucose measurements to rule out hypernatremia, hyponatremia, hyperglycemia, and hyperosmolar states as the cause of encephalopathy. The calcium level, magnesium level, phosphorus level, and parathyroid hormone should be assessed as they cause metabolic encephalopathy. Lactic acid level and toxicology screen should also be ordered. A lumbar puncture is not helpful for the diagnosis of UE; however, it may be required at a stage when no improvement is seen after renal replacement therapy. C-reactive protein (CRP) can be done to look into the possibility of infection if there is clinical suspicion of infection.

Neurological Evaluation  

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 and intermittent bursts of theta and delta waves with slow background activity. These findings are non-specific. EEG wave 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.[21]

Cognitive Tests

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.

Neuroimaging

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.[22] Abnormalities are found in the cortex, subcortical white matter, basal ganglia, and hippocampus.[23] 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. Posterior reversible leukoencephalopathy syndrome (PRES) may also be present at the same time.[24]
2. Bilateral basal ganglia involvement is seen in diabetic patients.[22]
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

Uremic encephalopathy is an absolute indication to initiate renal replacement therapy (RRT). Yanai et al. observed three cases of uremic encephalopathy in anuric patients getting peritoneal dialysis; all cases were resolved with the institution of hemodialysis.[25] Sometimes, a therapeutic trial with RRT is needed in the setting of uremia. Management of CKD should be implemented simultaneously, such as using erythropoiesis-stimulating agents, phosphate binders, calcium replacement, and nutrition modification. 

Providers should address the following factors when managing uremic encephalopathy, which is included in the standard management of any patient with ESRD:

• Adequacy of dialysis
• Correction of anemia
• Regulation of calcium and phosphate metabolism

There is clinical evidence that intermittent hemodialysis (HD) is more effective than continuous ambulatory peritoneal dialysis (CAPD). However, there is a danger of causing or precipitating dialysis disequilibrium syndrome (DDS) due to the risk of rapid osmotic changes at the start of HD.[26] Mannitol is used to prevent DDS in the first few HD sessions. Twenty-five grams of mannitol can be given for the first three sessions before starting hemodialysis.

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.[27]

Differential Diagnosis

Uremic encephalopathy is a diagnosis of exclusion. The following should be considered in the differential diagnosis:  

1. Wernicke-Korsakoff encephalopathy
2. Hypertensive encephalopathy
3. Hyperosmolar coma
4. Disequilibrium syndrome
5. Metabolic encephalopathy[28]
6. Sepsis 
7. Fluid and electrolyte disturbances, such as hyponatremia and hypermagnesemia
8. Drug toxicity 
9. Posterior reversible encephalopathy syndrome[4]
10. Osmotic demyelination syndrome
11. Hepatic encephalopathy
12. Hypoglycemia 

A mnemonic to remember a set of conditions that lead to diffuse cortical injury on MRI is “CRUMPLED.” In this mnemonic, C is for Creutzfeldt-Jakob disease, R stands for reversible cerebral vasoconstriction syndrome, U is for uremic encephalopathy, M is for mitochondrial cytopathy/encephalopathy, P stands for prolonged seizure/posterior reversible encephalopathy, L is for laminar necrosis hypoxic-ischemic injury, L stands for liver disease, E is for encephalitis (infectious), and D is for diabetes mellitus - hypoglycemia.

Prognosis

With the initiation of RRT, the clinical syndrome of uremic encephalopathy 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. Uremic encephalopathy is typically more severe in patients with acute kidney injury due to the neurotoxicity of nitrogenous solutes and other osmotically active toxins.[29]

Complications

Some of the complications of uremic encephalopathy are seizures, coma, and death. Upon initiation of renal replacement therapy, UE may be partially reversed. However, some cognitive changes may become permanent.

Consultations

A neurologist should be consulted if symptoms of uremic encephalopathy do not improve after the initiation of dialysis therapy. For patients with end-stage renal disease, it is worthwhile to consult a vascular surgeon for vascular access placement. For dietary modifications, refer patients with end-stage renal disease to a dietitian familiar with renal disorders.

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 uremic encephalopathy develops. To avoid malnutrition in end-stage renal disease, patients should maintain sufficient protein intake (1.2 g/kg/day) and initiate renal replacement therapy (despite the presence of encephalopathy).

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 must consider other diagnoses, such as hypertensive encephalopathy, hyperosmolar coma, metabolic encephalopathy, and drug toxicity. 

While the nephrologist is almost always involved in caring for patients with uremic encephalopathy, it is essential to have 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 in the 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 critical members of patient care, preventing medication-related problems and enhancing safe, effective medication use, as well as determining dosing intervals for drug effectiveness around the dialysis schedule. Radiologists also have an essential 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 the early identification of uremic encephalopathy, as is prompt RRT initiation to prevent complications and mortality.

The interprofessional care model, utilizing open communication between all team members (which includes accurate and updated records of all interventions and interactions with the patient), is crucial to optimal patient outcomes. [Level 5]