Uremic Encephalopathy

Etiology

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

Generally, uremic toxins build up in a patient's blood when they develop acute kidney injury due to various reasons. They either cannot clear solutes through renal replacement therapy or fail to respond to therapy. The causes of this buildup are extensive and include drugs, toxins, prolonged hypotension, dehydration, sepsis, and blood loss.[6][7] Uremic encephalopathy can also develop in patients with CKD when their eGFR falls due to acute insults such as infection, drugs, excessive vomiting, or diarrhea. Additionally, patients on hemodialysis can develop uremic encephalopathy if they receive inadequate dialysis due to factors like noncompliance or arteriovenous fistula dysfunction.[8]

Epidemiology

The absence of specific defining characteristics of uremia complicates data interpretation. However, severe encephalopathy appears to be rare in patients with progressive CKD, as most of them undergo renal replacement therapy before severe encephalopathy ensues. Uremic encephalopathy can also occur with acute kidney injury, where the decline in GFR is less predictable and more rapid.[4] Cognitive dysfunction is multifactorial, potentially stemming from vascular injury, endothelial inflammation, or direct effects of neurotoxins, and can affect up to 60% of patients with CKD. The cause and effect of the relationships between neurotoxins and cognitive dysfunction are uncertain. Therefore, it is challenging to estimate the prevalence of uremic encephalopathy. In a pediatric study, uremic encephalopathy was observed in 40% of patients with a blood urea nitrogen (BUN) level exceeding 90 mg/dL. As BUN levels increased, the propensity of these children to develop convulsions increased.[9]

Uremic encephalopathy significantly increases the morbidity and mortality in CKD patients.[1] Symptoms can be reversed by initiating dialysis and clearing toxic solutes in acute kidney injury. In patients with end-stage renal disease (ESRD), the condition is also reversible through dialysis or kidney transplantation. Severe complications, such as seizures or coma, can be fatal. Early recognition of neurological signs in patients with impaired renal function is crucial to prevent morbidity and mortality. Prompt initiation of dialytic therapy can reduce mortality rates.[10] Notably, racial predilection does not exist, and 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 the accumulation of neurotoxins.[3][5] Over 130 chemicals have been identified as potential neurotoxins.[11] These include 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 understand the functions of these chemicals in causing uremic encephalopathy. The European Uremic Toxins (EUTox) workgroup, an international consortium of academic and medical researchers, strives to understand these compounds' roles. These chemicals belong to diverse and unrelated groups, such as peptides, ions, and lipid and carbohydrate metabolism products. An ideal classification of uremic toxins does not exist, but based on their physicochemical properties, they may be classified as water-soluble, protein-bound, and middle molecules. Although no common pathway has been identified, 3 processes may contribute overall—an imbalance in inhibitory and excitatory neurotransmitters, neuronal degeneration, and vascular inflammation.[13]

According to a hypothesis, plasma and cerebrospinal fluid levels of glycine increase, whereas glutamine and gamma-aminobutyric acid (GABA) decrease. The accumulation of guanidino compounds, resulting from L-arginine metabolism, leads to the activation of excitatory N-methyl-D-aspartate (NMDA) receptors and further inhibits inhibitory GABA receptors.[2][14][15] Another proposed mechanism is hyperparathyroidism, which increases the calcium content in brain cells.[16] However, encephalopathy improves with dialysis, which does not immediately affect parathyroid hormone levels. Recently, a link between vascular endothelial dysfunction and cognitive dysfunction has been recognized, potentially contributing to the clinical syndrome of uremic encephalopathy.

The blood pressure regulatory neurons are located in the rostral ventrolateral medulla, which contains the presympathetic neurons. When exposed to high concentrations of uric acid, indoxyl sulfate, and methyl guanidine, RVLM neuronal activity increases. The subsequent use of antioxidant drugs results in the cessation of RVLM activity, which suggests that reactive oxidant species have a central role in developing the clinical syndrome of uremic encephalopathy. While urea is used as a surrogate marker for neurotoxins and is lowered with dialysis, there is no credible evidence linking urea directly to encephalopathy. Recent studies have shown that indoxyl sulfate can cause vascular inflammation and neurological symptoms.[17] The common mechanism appears to be oxidative stress.

Oxidative stress can alter mitochondrial function, leading to dysfunctional mitochondria that produce more uremic toxins, creating a self-perpetuating cycle.[11] The metabolism of purines and the urea cycle requires enzymes located within the mitochondria. Therefore, in patients with uremic encephalopathy, there is an acquired mitochondrial defect. As a result, uremic brains are less capable of utilizing ATP-requiring pathways compared to healthy brains. Reactive oxygen species accumulate due to mitochondrial dysfunction, further aggravating oxidative stress. This oxidative stress results in endothelial dysfunction, myelin injury, and nitration of brain proteins, leading to the production of more uremic toxins.[18]

History and Physical

Uremic encephalopathy is a clinical syndrome with no established diagnostic criteria. The clinical presentation is variable and depends on the rate of progression of the underlying kidney disease. In patients with a slow decline in eGFR, the primary signs include fatigue, anorexia, weight loss, and nausea. Cognitive dysfunction in these patients is slow, progressive, and subtle.[19] Symptoms may include restlessness, drowsiness, diminished concentration ability, 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.[20] A physical examination reveals cognitive dysfunction, including abnormalities in memory, judgment, and the ability to perform calculations. Hyperreflexia, asterixis, papilledema, and nystagmus are frequently present. Additionally, neuropathy and myopathy may also be observed.

Evaluation

Uremic encephalopathy is an absolute indication to start renal replacement therapy, making early diagnosis essential. This clinical syndrome has a variable and subtle presentation, and there is no confirmatory test, leading to delays in diagnosis. During the evaluation, it is crucial to exclude conditions that may mimic uremic encephalopathy, such as infection, osmotic demyelination, subdural hematomas, hypertensive encephalopathy, cerebrovascular accidents, and disequilibrium syndrome.

Laboratory Evaluation

Specific confirmatory tests to diagnose uremic encephalopathy do not exist. Renal function tests reveal markedly elevated BUN and creatinine levels in uremic encephalopathy.[21] The workup should be rapid and geared toward excluding other conditions that mimic uremic encephalopathy, which is ubiquitous in patients with advanced CKD. A complete blood count should be done to evaluate leucocytosis, which could indicate an underlying infection. Serum electrolyte and glucose measurements should be considered to rule out hypernatremia, hyponatremia, hyperglycemia, and hyperosmolar states as causes of encephalopathy. Calcium, magnesium, phosphorus, and parathyroid hormone levels should be assessed as they can worsen metabolic encephalopathy. Lactic acid levels and a toxicology screen should also be ordered. A lumbar puncture does not help diagnose uremic encephalopathy but may be required if no improvement is seen after renal replacement therapy to evaluate for other neurological conditions. C-reactive protein can be measured to investigate the possibility of infection if there is clinical suspicion of infection.

Neurological Evaluation  

The electroencephalogram (EEG) is nondiagnostic but is often performed an EEG is in patients to exclude underlying seizures. EEG findings in uremic encephalopathy include a loss of alpha frequency waves, overall slowing, and intermittent bursts of theta and delta waves with slow background activity. These findings are nonspecific. The degree of EEG wave slowing is directly proportional to the worsening renal function. After the initiation of dialysis, the EEG changes stabilize but may not return to baseline. Some improvement may occur over several months.[22]

Cognitive Tests

Cognitive tests that can be used include 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 scan of the brain can exclude focal lesions. Magnetic resonance imaging (MRI) studies in uremic patients show widespread brain involvement.[23] Abnormalities can be found in the cortex, subcortical white matter, basal ganglia, and hippocampus.[24] These extensive lesions result in a variable clinical presentation. Based on MRI findings, patients with uremic encephalopathy may be grouped into 3 types:

• Cortical and subcortical involvement, with posterior reversible leukoencephalopathy syndrome (PRES) potentially present concurrently.[25]
• Bilateral basal ganglia involvement is commonly observed in diabetic patients.[23]
• White matter involvement only, which is rare.

The presence of PRES in imaging studies performed for uremic encephalopathy suggests a close relationship between vascular and neuronal dysfunction, as described in the pathogenesis of uremic encephalopathy. A published case demonstrated that MRI changes, such as increased signal intensity, are reversible after several sessions of intermittent hemodialysis compared to continuous ambulatory peritoneal dialysis (CAPD). MRI changes involve multiple brain areas; currently, there is no evidence to delineate the reversible and nonreversible changes in functional imaging. In general, intermittent hemodialysis can clear uremic toxins faster than CAPD.

Treatment / Management

Uremic encephalopathy is an absolute indication to initiate renal replacement therapy. A study observed 3 cases of uremic encephalopathy in anuric patients undergoing peritoneal dialysis despite adequate Kt/V (where K is dialyzer clearance of urea [L/min], t is dialysis time [minutes], and V is the distribution volume of body fluids or urea [liters]). All cases were resolved with the initiation of hemodialysis. These patients also had low albumin levels and evidence of malnutrition, which could be contributing factors.[13] Often, a therapeutic trial with renal replacement therapy is warranted in the setting of uremia to evaluate for symptom improvement. Management of CKD should be implemented simultaneously, including using erythropoiesis-stimulating agents, phosphate binders, calcium replacement, and nutrition modifications. Providers should address the following factors when managing uremic encephalopathy, which are included in the standard management of any patient with ESRD:(B2)

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

Clinical evidence indicates intermittent hemodialysis is more effective than CAPD for solute clearance. However, this method carries the risk of causing or precipitating dialysis disequilibrium syndrome due to rapid osmotic changes at the start of intermittent hemodialysis.[26] Please see StatPearls' companion resource, "Dialysis Dysequilibrium Syndrome," for further information. Mannitol can prevent this condition in the first few intermittent hemodialysis sessions. Mannitol (25 g) can be administered for the first 3 sessions before starting hemodialysis. Studies have shown that the measured blood osmolality change is reduced by 60% with mannitol (a 10 mmol/kg fall in plasma osmolality was decreased to 4.3 mmol/kg with intravenous mannitol before intermittent hemodialysis). The symptoms of dialysis disequilibrium syndrome 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]

The key to avoiding uremic encephalopathy is initiating renal replacement therapy promptly. Most guidelines suggest making preparations for renal replacement therapy access or referral for renal transplant when the eGFR falls below 20 mL/min. Previously, the Fistula First initiative encouraged fistulas for all patients. However, the 2019 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines now endorse the concept of "right access, in the right patient, at the right time, for the right reasons" to provide more patient-centered care.[28](A1)

Differential Diagnosis

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

• Wernicke-Korsakoff encephalopathy
• Hypertensive encephalopathy
• Hyperosmolar coma
• Disequilibrium syndrome
• Metabolic encephalopathy [29]
• Sepsis 
• Fluid and electrolyte disturbances, such as hyponatremia and hypermagnesemia
• Drug toxicity 
• PRES [4]
• Osmotic demyelination syndrome
• Hepatic encephalopathy
• Hypoglycemia 

A mnemonic to remember a set of conditions that lead to diffuse cortical injury on MRI is “CRUMPLED.” In this mnemonic, C stands 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 or PRES, L stands for liver disease, E is for encephalitis/infectious, and D is for diabetes mellitus causing hypoglycemia.

Prognosis

With the initiation of renal replacement therapy, the clinical syndrome of uremic encephalopathy usually improves, although recovery may take days to weeks. EEG changes may require several months to recover and may not return to baseline. Some cognitive changes in the brain may be irreversible, underscoring the importance of initiating renal replacement therapy before the onset of uremic encephalopathy. Uremic encephalopathy is typically more severe in patients with acute kidney injury due to the neurotoxic effects of nitrogenous solutes and other osmotically active toxins.[30]

Complications

Some complications of uremic encephalopathy include seizures, coma, and death. Initiation of renal replacement therapy can partially reverse uremic encephalopathy; however, some cognitive changes may become permanent.