INTRODUCTION	Section 2 of 10
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Background: 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).

Pathophysiology: 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.

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.

Abnormalities that may be associated with UE include acidosis, hyponatremia, hyperkalemia, hypocalcemia, hypermagnesemia, overhydration, and dehydration.

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.

Frequency:

• In the US: 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.

• Internationally: 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.

Mortality/Morbidity: RF is fatal if untreated.

• UE reflects worsening renal function, with symptoms worsening as RF progresses. If untreated, UE progresses to coma and death.

• Patients need aggressive care to prevent complications and maintain homeostasis. They depend on intensive care and dialysis. In the United States, more than 200,000 patients are currently receiving hemodialysis.

Race: 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.

Sex: Incidences are equal in men and woman.

Age: 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.

	CLINICAL	Section 3 of 10
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History:

• UE is a consequence of RF.

• Symptoms begin insidiously and are often noticed not by the patients but by their family members or caregivers.

• In many cases, impairment of the nervous system provides the first indication of metabolic derangements.

• Symptoms may progress slowly or rapidly.

• Changes in sensorium include loss of memory, impaired concentration, depression, delusions, lethargy, irritability, fatigue, insomnia, psychosis, stupor, catatonia, and coma.

• Patients may complain of slurred speech, pruritus, muscle twitches, or restless legs.

Physical: 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:

• Myoclonic jerks, twitches, or fasciculations (ie, uremic twitch-convulsive syndrome postulated by Adams et al in 1997)

• Asterixis

• Dysarthria

• Agitation

• Tetany

• Seizures, usually generalized tonic-clonic

• Confusion, stupor, and other alterations in mental status

• Coma

• Dialysis encephalopathy (or dialysis dementia) is a subacute, progressive, and often-fatal disease that occurs in patients undergoing long-term hemodialysis.

• Dialysis encephalopathy is believed to be part of a multisystem disease that includes encephalopathy, osteomalacic bone disease, proximal myopathy, and anemia.

• One half of patients have nonspecific GI complaints. The etiology is controversial; it has been attributed to aluminum in the water used in the dialysate.

• Symptoms include dysarthria, apraxia, personality changes, psychosis, myoclonus, seizures and, finally, dementia.

• In most cases, the condition progresses to death in 6 months.

• Dialysis encephalopathy may be a manifestation of aluminum toxicity.

• Dialysis disequilibrium syndrome occurs in patients receiving hemodialysis.

• Symptoms include headache, nausea, emesis, blurred vision, muscular twitching, disorientation, delirium, hypertension, tremors, and seizures.

• The condition tends to be self-limited and subsides over several hours.

• Dialysis disequilibrium syndrome is attributed to a reverse urea effect. Urea is cleared more slowly from the brain than from the blood, an effect that causes an osmotic gradient leading to the net flow of water into the brain and to transient cerebral edema.

• Complications of renal transplantation can lead to UE. This occurrence has become more common as more patients are receiving renal transplants.
  • This condition is characterized by edema of the white matter.

  • Patients are at risk for primary brain lymphoma and opportunistic infections because of long-term immunosuppression.

• 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.

• Uremic polyneuropathy is the most common neurologic complication of RF.

Causes:

• 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.