Uremic brain

The recent use of advanced neuroimaging techniques has led to substantial in vivo study of uremic brain in humans (Arieff et al., 1994). Acute and subacute movement disorders have been observed in patients with ESRD. These have been associated with bilateral basal gangUa and internal capsule lesions (Wang et al., 2004). Cerebral atrophy has been observed in chronic hemodialysis patients, and it tends to worsen as dialysis therapy continues (Savazzi, 1988 Savazzi et al., 1995). Cerebral atrophy had previously been thought to be associated with dialysis donentia, but this is apparently not the case (Mahurkar et al., 1978). ESRD has also been reported to lead to deterioration of vision. Some cases are associated with uremic pseudotumor cerebri, and in these cases, surgical optic nerve fenestration may improve visual loss (Guy et al., 1990 Korzets et al., 1998). 

Chronic Dialysis Dependent Encephalopathy Radiologic and Pathologic Examination of Uremic Brain... 

Uremia results in increased permeability of the blood-brain barrier to sucrose and insulin K+ transport is enhanced whereas Na+ transport is impaired. There is an increase in brain osmolarity in acute renal failure due to the increase in urea concentrations. However, in contrast to acute renal failure, the increase in osmolarity in chronic renal failure results from the presence of idiogenic osmoles in addition to urea. CBF is increased in uremic patients but CMR02 and CMR are decreased. In the brains of rats with acute renal failure, ATP, phosphocreatine and glucose are increased whereas AMP, ADP and lactate are decreased, most probably as a result of decreased energy demands. 

Fraser, C. L. Neurologic manifestations of the uremic state. In A. I. Arieff and R. C. Griggs (eds), Metabolic Brain Dysfunction in Systemic Disorders. Boston Little, Brown Co., 1992, pp. 139-166. 

Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T (2002) Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin Its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem 83 57-66... 

Bell, W. R., Braine, H. G., Ness, P. M., and Kidder, T. S., Improved survival in toom-botic thrombocytopenic purpura hemolytic-uremic-syndrome-cUnical experience in 108 patients. 

When there is inadequate elimination of aluminum from the body, as in nondialyzed uremic patients, increased aluminum concentrations are detected in serum, bone tissue, liver, spleen, brain, and skeletal muscle (Alfrey et al. 1980 Arieff et al. 1979). In hemodialysis patients exposed by infusion to large amounts of aluminum over long periods of time (with inadequate removal of aluminum by the kidneys and dialysis machines), increased aluminum concentrations are observed mostly in the spleen, followed by the liver and skeletal system (Alfrey 1980 Alfrey et al. 1980). 

Although there is no evidence that neuropsychiatric complications of macrolides develop more readily in uremic patients, several factors may predispose toward these adverse effects, such as reduced drug clearance, altered plasma protein binding, different penetration of drug across the blood-brain barrier, and an increased propensity for drug interactions. 

Thrombotic thrombocytopenic purpura is a rare acute or subacute disease in adults, rather similar to the hemolytic uremic syndrome in children, in which there is systemic malaise, fever, skin purpura, renal failure, hematuria and proteinuria. Hemorrhagic infarcts caused by platelet microthrombi occur in many organs in the brain they may cause stroke-like episodes (Matijevic and Wu 2006) although more commonly there is global encephalopathy. The blood film shows thrombocytopenia, hemolytic anemia and fragmented red cells. The differential diagnosis includes infective endocarditis, idiopathic thrombocytopenia, heparin-induced thrombocytopenia with thrombosis, systemic lupus erythematosus, non-bacterial thrombotic endocarditis and disseminated intravascular coagulation. 

When behavioral recordings are coupled with electroencephalography, in a digital format, the so-called Video-EEG, allows to prove, in freely moving animals, the behavioral and EEG effects after star fruit ingestion or after local apphcation in specific brain regions of either, the crude or the purified toxin. In the first case the hypothesis that experimentally uremic animals, induced by HgCl, a known model of renal failure [48], will reproduce the star fruit intoxication effects found in the patients can be tested (see above). In the second case, the hypothesis that the crude or purified toxin per se will be able to induce behavioral and EEG activity compatible with brain hyperexcitability, possibly associated to seizures is tested. As a positive effect, the latter experimental protocol (with not relationships with renal alterations) will even validate the potential of this neurotoxin as a new tool in the neuroscience field. 

Hosoya K, Tachikawa M (2011) Roles of organic anion/cation transporters at the blood-brain and blood-cerebrospinal fluid barriers involving uremic toxins. Clin Exp Nephrol 15 478 85... 

Dialysis dysequilibrium is not seen often nowadays. It may occur in very uremic patients during the first dialysis, particularly with high-flux dialysis or very rapid blood flow. Its etiology is not clear, but is probably related to increased cerebrospinal fluid pressure and cerebral edema. The possible role of urea has already been discussed (see Section 3.1). Another hypothesis is that the brain cells of uremic patients produce idiogenic osmoles to prevent water loss to the hyperosmolar extracellular fluid. When high-flux dialysis rapidly decreases extracellular fluid osmolality, it may cause a water shift into the brain (B22). 

M29. Matsumoto, M., Kishikawa, H and Mori, A., Guanidino compounds in the sera of uremic patients and in the sera and brain of experimental uremic rabbits. Biochem. Med. 16, 1-8 (1976). 

Fig. 9.7 (a) Activation of the astrocytic mitochondrial PTBR results in the synthesis of neurosteroids such as allopregnanolone with potent agonist actions at the GABA-A receptor complex, (b) Allopregnanolone levels are increased in autopsied brain tissue from cirrhotic patients who died in hepatic coma (HE) but not in non-encephalopathic cirrhotic patients (LD), or in a patient who died in uremic coma (UC). Modified from Ahboucha et al., 2005)... 

In general then, studies of brain tissue from both intact animal models of uremia and humans with renal lailure have revealed many different biochemical abnormalities associated with the uranic state. However, such investigations have not as yet revealed much about the fundamental mechanisms that might induce such abnormalities. Such studies probably will have to be done in isolated cell systems or subcellular systems from the brain. These systems have the advantage of permitting one to study isolated manifestations of the uremic state while removing the numerous potential confounding influences present in an in vivo model. 

Arieff AI, Guisado R Massry SG. (1975). Uremic encephalopathy Studies on biochemical alterations in the brain. Kidney Int 7, S194-S200. 

De Deyn PP, Marescau B, D Hodge R, Possemiers I, Nagler J Mahler C. (1995). Guanidino compound levels in brain regions of non-dialyzed uremic patients. Neurochem Int 27, 227-237. 

Mahoney CA, Samacki P Arieff Al. (1984). Uremic encephalopathy Role of brain energy metabolism. Am J Physiol 247 (Reneil Fluid Electrolyte Physiol. 16), F527-F532. 

Minkoff L, Gaertner M, Darah C, Merder C Levin ML. (1972). Inhibition of brain sodium-potassium ATPase in uremic rats. J Lab Clin Med 80, 71-78. 

Van den Noort S, Eckel RE, Brine K Hrdlicka JT. (1968). Brain metabohsm in uremic and adenosine-infused rats. J CUn Invest 47, 2133-2142. 

Verkman AS Fraser CL. (1986). Water and non-electrolyte permeability in brain synaptosomes isolated from normal and uremic rats. Am J Physiol 250, R306-R312. 

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