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. 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.
Epidemiology
Frequency
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.
Mortality/Morbidity
RF is fatal if untreated.
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UE reflects worsening renal function, with symptoms worsening as RF progresses. If untreated, UE progresses to coma and death.
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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.
Demographics
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.
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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.
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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-P3, P3=O1, Fp2-F4, F4-C4, C4-P4, P4-O2, Fz-Cz, ECG.
