Uremia describes the final stage of progressive renal insufficiency and the resultant multiorgan failure. It results from accumulating metabolites of proteins and amino acids and concomitant failure of renal catabolic, metabolic, and endocrinologic processes. No single metabolite has been identified as the sole cause of uremia. Uremic encephalopathy (UE) is one of many manifestations of renal failure (RF).
The exact cause of UE is unknown. Accumulating metabolites of proteins and amino acids affect the entire neuraxis. Several organic substances accumulate, including urea, guanidine compounds, uric acid, hippuric acid, various amino acids, polypeptides, polyamines, phenols and conjugates of phenols, phenolic and indolic acids, acetoin, glucuronic acid, carnitine, myoinositol, sulfates, phosphates, and middle molecules. Levels of some of the guanidine compounds, including guanidinosuccinic acid, methylguanidine, guanidine, and creatinine, increase in patients with uremia who are or who are not receiving dialysis. Endogenous guanidino compounds have been identified to be neurotoxic.[1]
Patients with terminal RF have >100-fold increases in levels of guanidinosuccinic acid and guanidine, 20-fold increases in levels of methylguanidine, and 5-fold increase in levels of creatinine in various regions of the brain. Disturbance in the kynurenic pathway, by which tryptophan is converted to neuroactive kynurenines, has also been implicated. Levels of 2 kynurenines, 3-hydroxykynurenine and kynurenine, are elevated in rats with chronic renal insufficiency; these changes lead to alterations in cellular metabolism, cellular damage, and eventual cell death. Kynurenine can induce convulsions. Middle-molecules, a series of small protein-bound and nonprotein-bound molecules, such as β2-microglobulin, have been identified as uremic toxins.[2]
Abnormalities that may be associated with UE include acidosis, hyponatremia, hyperkalemia, hypocalcemia, hypermagnesemia, overhydration, and dehydration. Acute renal injury has been found in mice with increased neuronal pyknosis and microgliosis in the brain. Acute renal injury also led to increased levels of the proinflammatory chemokines keratinocyte-derived chemoattractant and G-CSF in the cerebral cortex and hippocampus, as well as increased expression of glial fibrillary acidic protein in astrocytes. Acute renal injury led to both soluble and cellular inflammation in the brain, affecting the CA1 region of the hippocampus foremost. Acute renal injury leads to increase in brain microvascular leakage.[3, 4]
No single abnormality is precisely correlated with the clinical features of UE. Increased levels of glycine, organic acids (from phenylalanine), and free tryptophan and decreased levels of gamma-aminobutyric acid (GABA) in the CSF may be responsible for early phases of the disorder. In rats with RF, brain levels of creatine phosphate, adenosine triphosphate (ATP), and glucose are increased, whereas levels of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and lactate are decreased. This finding suggests that the uremic brain uses less ATP and produces less ADP, AMP, and lactate than healthy brains, consistent with a generalized decrease in metabolic function.
Transketolase, found mainly in myelinated neurons, is a thiamine-dependent enzyme of the pentose phosphate pathway; it maintains axon-cylinder myelin sheaths. Plasma, CSF, and low-molecular-weight (< 500 Da) dialysate fractions from patients with uremia substantially inhibit this enzyme. Erythrocyte transketolase activity is lower in nondialyzed patients than in dialyzed patients. Guanidinosuccinic acid can inhibit transketolase.
Synaptosome studies of uremic rats have shown altered function of the sodium ATP and other metabolic pumps. Methylguanidine can induce a condition similar to UE that includes seizures and uremic twitch-convulsive syndrome. Guanidinosuccinic acid can also inhibit excitatory synaptic transmission in the CA1 region of the rat hippocampus, an effect that may contribute to cognitive symptoms in UE.
Guanidinosuccinic acid, methylguanidine, guanidine, and creatinine inhibited responses to GABA and glycine (inhibitory amino acids) in cultured mouse neurons. Guanidino compounds (GCs) inhibit nitric oxide synthase (NOS) modulators in vivo and in vitro. Accumulation of asymmetric dimethylarginine (ADMA), a NOS inhibitor, has been observed in patients with uremia; this accumulation induces hypertension and possibly increases ischemic vulnerability to the uremic brain.
UE involves many hormones, levels of several of which are elevated. Such hormones include parathyroid hormone (PTH), insulin, growth hormone, glucagon, thyrotropin, prolactin, luteinizing hormone, and gastrin. In healthy dogs, high levels of PTH produce CNS changes like those seen in uremia. PTH is thought to promote the entry of calcium into neurons, which leads to the changes observed.
A combination of factors, including increased calcium and decreased GABA and glycine activity, leads to a distorted balance of excitatory and inhibitory effects that contributes to systemic changes associated with UE.
United States
The prevalence of UE is difficult to determine. UE may manifest in any patient with end-stage renal disease (ESRD), and directly depends on the number of such patients. In the 1990s, more than 165,000 people were treated for ESRD, compared with 158,000 a decade earlier. In the 1970s, the number was 40,000. As the number of patients with ESRD increased, presumably so did the number of cases of UE. On a yearly basis, 1.3 per 10,000 patients develop ESRD.
For related information, see Medscape's End-Stage Renal Disease Resource Center.
International
The worldwide prevalence is unknown. In western Europe and in Japan (ie, countries with healthcare systems similar to that of the United States), statistics parallel to those of United States are expected. In general, the care of patients with UE depends on costly intensive care and dialysis that is not available in developing nations.
RF is fatal if untreated.
RF is more common in African Americans than in other races. Of all patients in the Medicare ESRD treatment program in 1990, 32% were African American, though African Americans account for only 12% of the US population. The overall incidence of ESRD is 4 times greater in African Americans than in whites.
Incidences are equal in men and woman.
People of all ages can be affected, but the fastest growing group with ESRD is the elderly, ie, persons older than 65 years. RF has a proportionally increased prevalence in this group compared with any other age group.
See the list below:
Physical findings are variable and depend on the severity of the encephalopathy. Neurologic findings range from normal to a comatose state. Cases of Wernicke syndrome associated with UE have been described in the literature, and Wernicke syndrome has been observed in patients with UE, dialysis dementia, or dialysis disequilibrium syndrome.
Findings include the following:
Some patients undergoing long-term dialysis acquire dialysis encephalopathy (or dialysis dementia), which is a subacute, progressive, and often fatal disease.[6] Aluminum toxicity either from aluminum phosphate salts or from aluminum in the dialysate were linked to the pathogenesis of dialysis dementia. Starting in the early and mid 1980s, aluminum was actively removed from the dialysate with a large reduction in the incidence of dialysis dementia.
Dialysis disequilibrium syndrome occurs in patients receiving hemodialysis.
Posterior reversible leukoencephalopathy syndrome (PRLS), also called reversible leukoencephalopathy syndrome, can occur at any age and can manifest with seizures (either generalized or focal), visual hallucinations, headaches, mental status impairment, and cortical blindness. It is not limited to uremic encephalopathy, but can also be seen in liver and renal transplant patients, pre-eclampsia, hypertension associated with renal disease, or other immunosuppressed states. The characterisitc MRI finding is diffuse attenuation in the cerebral white matter, and may include the brainstem and cerebellum. The disorder is self-limiting and improves if hypertension is controlled.[7]
Complications of renal transplantation can lead to UE. This occurrence has become more common as more patients are receiving renal transplants.
Rejection encephalopathy has been observed in patients undergoing transplantation. They have systemic features of acute graft rejection, more than 80% of whom have symptoms in the first 3 months after transplantation. Overall prognosis is good, with rapid recovery after treatment of the rejection episode. The presumed pathology is cytokine production secondary to the rejection process.
Uremic polyneuropathy is the most common neurologic complication of RF.
The exact cause of UE is unknown.
Accumulation of metabolites and, perhaps, imbalance in excitatory and inhibitory neurotransmitters are possible etiologies.
PTH and abnormal calcium control have also been identified as possible important contributing factors.
Blood tests reveal electrolyte abnormalities and abnormal renal function. PTH and calcium levels are high.
Results of routine CSF studies tend to be normal.
Brain imaging is of limited value. However, case reports exist of isolated cortical, centrum semiovale, basal ganglia, and brainstem involvement revealed by magnetic resonance imaging. The scans of such patients may show high signal either on diffusion-weighted imaging (WDWI) or on fluid-attenuated inversion recovery (FLAIR) imaging.[8, 9]
Brain SPECT is of limited benefit, however, a recent article describes a uremic patient with end-stage renal failure with bilateral basal ganglia decreased uptake. The patient had Parkinsonism, which was attributed to complications from uremia.[10]
EEG (especially serial EEG) is useful in assessing patients and in monitoring their progress.
View Image | EEG in a 56-year-old man with uremic encephalopathy. He became increasingly lethargic, requiring intubation. EEG shows absence of a posterior dominant.... |
View Image | EEG in a 56-year-old man with uremic encephalopathy. From top to bottom: Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, Fp1-F3, F3-C3, C3-P.... |
Evoked-potential studies are of limited value, revealing only nonspecific changes or normal patterns.
See the list below:
Brain histologic findings in UE include meningeal fibrosis, glial changes, edema, vascular degeneration, focal and diffuse neuronal degeneration, and focal demyelination. Small infarcts are also seen and are probably due to hypertension or focal necrosis. Cerebellar acute granule cell necrosis is observed.
Patients with dialysis dementia have spongiform changes in the outer 3 cortical layers, with elevated aluminum levels in the cerebral cortex. Other changes include neuronal loss, accumulation of lipofuscin pigment, and neurofibrillary degeneration in the motor cortex and in the red, dentate, and olivary nuclei.
The medical care of uremic encephalopathy (UE) includes correcting the metabolic disturbance, which usually requires dialysis (hemodialysis or peritoneal dialysis) or renal transplantation. Symptoms improve as renal function improves.
The role of surgery in managing UE is limited to cases involving renal transplantation, neurosurgical care for subdural hematoma or intracranial hemorrhage, and vascular access.
Consultation with the following may prove helpful:
In general, patients with UE are ill, and in the acute phase, their activity is limited to bed rest.
Patients need close follow-up in the acute stage of uremic encephalopathy. After the underlying problem is treated properly, the symptoms should resolve.
Levels of anticonvulsant drugs must be closely monitored to prevent toxicity.
In cases of intracranial hemorrhage, serial head neuroimaging may be necessary.
Transfer to a facility with staff and equipment for further evaluation and care may be necessary.
As always, trained personnel with appropriate monitoring should perform the transfer.
To ensure that treatment is initiated early, instruct patients and their family members and caregivers about the need for prompt medical evaluation when mental status changes occur.
EEG in a 56-year-old man with uremic encephalopathy. He became increasingly lethargic, requiring intubation. EEG shows absence of a posterior dominant alpha rhythm and diffuse bilateral slowing with mixed theta- and delta-frequency signal. A single sharp wave is present in the left occipital region, phase reversing at O1. From top to bottom: Fp1-F7, F7-T3, T3-T5, T5-O1, O1-O2, O2-T6, T6-T4, T4-F8, F8-Fp2, Fp2-Fp1, F3-C3, C3-P3, P3-O1, F4-C4, C4-P4, P4-O2, Fz-Cz, and ECG.
EEG in a 56-year-old man with uremic encephalopathy. He became increasingly lethargic, requiring intubation. EEG shows absence of a posterior dominant alpha rhythm and diffuse bilateral slowing with mixed theta- and delta-frequency signal. A single sharp wave is present in the left occipital region, phase reversing at O1. From top to bottom: Fp1-F7, F7-T3, T3-T5, T5-O1, O1-O2, O2-T6, T6-T4, T4-F8, F8-Fp2, Fp2-Fp1, F3-C3, C3-P3, P3-O1, F4-C4, C4-P4, P4-O2, Fz-Cz, and ECG.