Dialysis Encephalopathy Syndrome Research Articles

Dementia in patients undergoing long-term dialysis: aetiology, differential diagnoses, epidemiology and management.

Dementia in patients undergoing long-term dialysis has not been clearly defined; however, four different entities have been described. Uraemic encephalopathy is a complication of uraemia and responds well to dialysis. Dialysis encephalopathy syndrome, the result of acute intoxication of aluminium caused by the use of an aluminium-containing dialysate, was a common occurrence prior to 1980. However, using modern techniques of water purification, such acute intoxication can now be avoided. Dialysis-associated encephalopathy/dementia (DAE) is always associated with elevated serum aluminium levels. Pathognomonic morphological changes in the brain have been described, but the mechanism for the entry of aluminium into the CNS is incompletely understood. The mechanisms involved in the pathogenesis of the neurotoxicity associated with aluminium are numerous. Although only a very small fraction of ingested aluminium is absorbed, the continuous oral aluminium intake from aluminium-based phosphate binders, and also of dietary or environmental origin, is responsible for aluminium overload in dialysis patients. Age-related dementia, especially vascular dementia, occurs in patients undergoing long-term dialysis as frequently as it does in the general population. The differential diagnoses of dialysis-associated dementias should include investigation for metabolic encephalopathies, heavy metal or trace element intoxications, and distinct structural neurological lesions such as subdural haematoma, normal pressure hydrocephalus, stroke and, particularly, hypertensive encephalopathy and multi-infarct dementia. To prevent DAE, dietary training programmes should aim to achieve the lowest phosphate intake and pharmacological tools should be used to keep serum phosphate levels below 2 mmol/L. To prevent vascular dementia, lifestyle modification should be undertaken, including optimal physical activity and fat intake, nicotine abstinence, and targeting optimal blood glucose, cholesterol and triglyceride levels, and blood pressure, to those outlined in current recommendations.

Technical Aspects of Quantification of Aluminum

Aluminum has been implicated as a contributing factor to dialysis encephalopathy syndrome (DES) and osteomalacic osteodystrophy. Monitoring of its level together with i-PTH, desferoxamine infusion test, or bone biopsy gives the degree of intoxication. Specimens for aluminum must be collected in containers washed in nitric acid or disodium EDTA to avoid contamination. Determination is made with flameless atomic absorption spectrometry or neutron activation. Various experimental conditions for the former together with discussion on their merits and shortcomings are given. Included are protein precipitation, matrix modification, background correction, and sampling technique.

Relationship of Aluminum to Neurocognitive Dysfunction in Chronic Dialysis Patients

• Aluminum has been proposed as the causative agent in dialysis encephalopathy syndrome. We prospectively assessed whether other, less severe, neuropsychologic abnormalities were also associated with aluminum. A total of 16 patients receiving chronic dialytic therapy were studied. The deferoxamine infusion test (DIT) was used to assess total body aluminum burden. Neurologic function was evaluated by quantitative measures of asterixis, myoclonus, motor strength, and sensation. Cognitive function was assessed by measures of dementia, memory, language, and depression. There were four patients with a positive DIT (greater than 125 μg/L increment in serum aluminum) that was associated with an increase in the number of neurologic abnormalities observed, as well as an increase in severity of myoclonus, asterixis, and lower extremity weakness. Patients with a positive DIT also showed significant impairment in memory; however, no differences were noted on tests of dementia, depression, or language. There was no significant correlation between sex, age, presence of diabetes, mode of dialysis, years of chronic renal failure, years of dialysis or years of aluminum ingestion and any neurologic or neurobehavioral measurement, serum aluminum level, or DIT. These changes may represent early aluminum-associated neurologic dysfunction. (<i>Arch Intern Med</i>1988;148:2169-2172)

Relationship of aluminum to neurocognitive dysfunction in chronic dialysis patients

Aluminum has been proposed as the causative agent in dialysis encephalopathy syndrome. We prospectively assessed whether other, less severe, neuropsychologic abnormalities were also associated with aluminum. A total of 16 patients receiving chronic dialytic therapy were studied. The deferoxamine infusion test (DIT) was used to assess total body aluminum burden. Neurologic function was evaluated by quantitative measures of asterixis, myoclonus, motor strength, and sensation. Cognitive function was assessed by measures of dementia, memory, language, and depression. There were four patients with a positive DIT (greater than 125 micrograms/L increment in serum aluminum) that was associated with an increase in the number of neurologic abnormalities observed, as well as an increase in severity of myoclonus, asterixis, and lower extremity weakness. Patients with a positive DIT also showed significant impairment in memory; however, no differences were noted on tests of dementia, depression, or language. There was no significant correlation between sex, age, presence of diabetes, mode of dialysis, years of chronic renal failure, years of dialysis or years of aluminum ingestion and any neurologic or neurobehavioral measurement, serum aluminum level, or DIT. These changes may represent early aluminum-associated neurologic dysfunction.

The metabolism of aluminum and aluminum-related encephalopathy.

The dialysis encephalopathy syndrome is at once the most widely recognized and most severe manifestation of aluminum toxicity. Evidence linking this syndrome and aluminum intoxication is virtually incontrovertible. The syndrome is characterized by speech and motor difficulties, dementia, and seizures. Less widely recognized symptoms include subtle changes in cognition and personality and directional disorientation. Since the widespread use of water treatment, aluminum exposure in the dialysis population has been primarily via intravenous (IV) medications and oral aluminum-containing, phosphate-binding antacid gels. In addition to the encephalopathy syndrome, aluminum has been linked to toxicity in bone, parathyroid gland, RBC, and kidney. These organ toxicities seem to be the result of specific protein enzyme inhibition. Currently identified factors that affect aluminum accumulation and modulate aluminum balance include uremia, renal function, parathyroid hormone withdrawal and suppression, 1,25-dihydroxycholecalciferol, and serum aluminum binding. Impaired renal function is not a prerequisite for increased tissue aluminum burdens. It is likely that aluminum-related disease will be increasingly observed in populations other than those with chronic renal failure.

8 Aluminium toxicity in chronic renal insufficiency

Aluminium is a ubiquitous element in the environment and has been demonstrated to be toxic, especially in individuals with impaired renal function. Not much is known about the biochemistry of aluminium and the mechanisms of its toxic effects. Most of the interest in aluminium has been in the clinical setting of the haemodialysis unit. Here aluminium toxicity occurs due to contamination of dialysis solutions, and treatment of the patients with aluminium-containing phosphate binding gels. Aluminium has been shown to be the major contributor to the dialysis encephalopathy syndrome and an osteomalacic component of dialysis osteodystrophy. Other clinical disturbances associated with aluminium toxicity are a microcytic anaemia and metastatic extraskeletal calcification. Aluminium overload can be treated effectively by chelation therapy with desferrioxamine and haemodialysis. Aluminium is readily transferred from the dialysate to the patient's bloodstream during haemodialysis. Once transferred, the aluminium is tightly bound to non-dialysable plasma constituents. Very low concentrations of dialysate aluminium in the range of 10-15 micrograms/l are recommended to guard against toxic effects. Very few studies have been directed towards the separation of the various plasma species which bind aluminium. Gel filtration chromatography has been used to identify five major fractions, one of which is of low molecular weight and the others appear to be protein-aluminium complexes. Recommendations on aluminium monitoring have been published and provide 'safe' and toxic concentrations. Also, the frequency of monitoring has been addressed. Major problems exist with the analytical methods for measuring aluminium which result from inaccurate techniques and contamination difficulties. The most widely used analytical technique is electrothermal atomic absorption spectrometry which can provide reliable measurements in the hands of a careful analyst.

Consequences of avascular necrosis of the femoral head in aluminium-related renal osteodystrophy and the role of endochondral ossification in the repair process.

A patient with chronic renal failure, a dialysis encephalopathy syndrome and renal osteodystrophy associated with aluminium intoxication developed an avascular necrosis of the left femoral head. Histological examination of the excised head confirmed the zone of avascular necrosis and demonstrated an exuberant formation of cartilage around this zone. Calcification was sparse and the cartilage exhibited histological features similar to those seen in classical rickets. Histochemical and electron probe x-ray microanalysis demonstrated aluminium in the matrix around hypertrophic chondrocytes, at the tide mark of articular cartilage and at the mineralised tissue/osteoid interface of trabecular bone. Aluminium, therefore, preferentially localises at sites of calcification and possibly exerts an inhibitory effect on this reaction. This is taken to account for the relative failure of endochrondral ossification and the development of a rachitic appearance. A comparison with five other examples of avascular necrosis of the femoral head (occurring after renal transplantation, as an idiopathic phenomenon and as a complication of steroid therapy) showed that, in addition to the more commonly described appositional bone formation, cartilage formation and endochondral ossification were present in three of these comparison cases, although less prominent and of considerably less degree than in the main case.

Inhibition of corticosterone binding in vitro, in rabbit hippocampus, by chromatin bound aluminum.

Brains of patients with senile dementia of the Alzheimer type and with the dialysis encephalopathy syndrome, exhibit elevated aluminum levels. In Alzheimer's disease and in the experimental aluminum induced encephalopathy, intracellular aluminum is associated with nuclear chromatin. The work reported here was undertaken to test whether chromatin bound aluminum in hippocampus of the rabbit interferes with nuclear binding of corticosterone-receptor complexes. The results showed that the mean binding of corticosterone decreased from 460 +/- 71 fmol/mg DNA in controls, to 343 +/- 81 fmol/mg DNA in hippocampal nuclei from aluminum treated rabbits, representing a decrease of 25%. This reduction occurred in the absence of aluminum induced neurofibrillary degeneration and indicates a possible functional consequence of the presence of aluminum on chromatin, and importantly, in the absence of morphological changes.

Senile plaques and tangles in dialysis dementia.

The brains of 7 patients treated with hemodialysis were studied. Four of these patients had the dialysis encephalopathy syndrome (DES). Senile plaques and or neurofibrillary tangles were found in 5 of the 7 cases, 3 with and 2 without DES. One case of each group had plaques to an extent compatible with that in Alzheimer's disease, though of a different distribution. Neurofibrillary tangles were generally sparse. Plaques and tangles, both containing paired helical filaments, are the principal changes in Alzheimer's disease. Aluminum has been implicated as a possible etiologic agent behind the paired helical filaments in Alzheimer's disease, where raised cerebral aluminum contents have been demonstrated. Aluminum is known to be increased in the central nervous system also in DES, most likely as a consequence of procedures in connection with the hemodialysis. The finding of neurofibrillary tangles and senile plaques in hemodialyzed patients, some of which have developed DES, may therefore support the theories concerning aluminum as an etiological agent for cerebral changes in Alzheimer's disease.

Aluminium toxicity during regular haemodialysis.

In the west of Scotland the incidence of dialysis encephalopathy has been confined to three geographical areas where the concentration of aluminium in the water supply is greatly increased owing to the addition of aluminium sulphate. Eight patients with encephalopathy who dialysed at home in these areas had greatly increased serum aluminium concentrations, and a significant correlation was found between serum aluminium concentrations and the concentrations of aluminium in the water supply. This study provides further evidence that the dialysis encephalopathy syndrome is due to aluminium intoxication, the major source of aluminium being the water supply from which dialysis fluid prepared.

Factors Affecting Tissue Aluminum Concentration

Elevated concentration of aluminum has been reported in serum, whole blood and tissue samples of patients with renal insufficiency. Evidence incriminating aluminum as a neurotoxin among the dialysis population is strong. The source of this aluminum has not been clearly defined, although both gastrointestinal and parenteral routes may be involved. Data from this laboratory suggest that an effect of parathyroid hormone on tissue aluminum burdens may, in part, explain why only certain patients exposed to high dialysate aluminum develop the dialysis encephalopathy syndrome and the occasional occurrence of this syndrome in the absence of dialysis or increased dialysate aluminum.

3107. Aluminium toxicity in renal failure: Alfrey, A. C, LeGendre, G. R. & Kaehny, W. D. (1976). The dialysis encephalopathy syndrome. Possible aluminum intoxication. New Engl. J. Med. 294, 184.

3107. Aluminium toxicity in renal failure: Alfrey, A. C, LeGendre, G. R. & Kaehny, W. D. (1976). The dialysis encephalopathy syndrome. Possible aluminum intoxication. New Engl. J. Med. 294, 184.

Assessment of radiological changes in the hands and feet in rheumatoid arthritis. Their correlation with prognosis.

A patient with chronic renal failure, a dialysis encephalopathy syndrome and renal osteodystrophy associated with aluminium intoxication developed an avascular necrosis of the left femoral head. Histological examination of the excised head confirmed the zone of avascular necrosis and demonstrated an exuberant formation of cartilage around this zone. Calcification was sparse and the cartilage exhibited histological features similar to those seen in classical rickets. Histochemical and electron probe x-ray microanalysis demonstrated aluminium in the matrix around hypertrophic chondrocytes, at the tide mark of articular cartilage and at the mineralised tissue/osteoid interface of trabecular bone. Aluminium, therefore, preferentially localises at sites of calcification and possibly exerts an inhibitory effect on this reaction. This is taken to account for the relative failure of endochrondral ossification and the development of a rachitic appearance. A comparison with five other examples of avascular necrosis of the femoral head (occurring after renal transplantation, as an idiopathic phenomenon and as a complication of steroid therapy) showed that, in addition to the more commonly described appositional bone formation, cartilage formation and endochondral ossification were present in three of these comparison cases, although less prominent and of considerably less degree than in the main case.