The neurological problems that patients with chronic renal failure face are relatively new to the medical world. Although dialysis was technically feasible in the 1940’s, it has only been since 1960 that techniques and equipment have been developed to make long term dialysis available as a practical treatment for end stage renal failure. Further, it has only been since 1973 when Medicare legislation was amended to include patients with chronic renal failure; and the expansion of hospital dialysis services in addition to the emergence of private outpatient hemodialysis clinics, that hemodialysis has become available for the vast majority with end stage renal failure. By increasing services to many more patients, our experience with the problems associated with long term dialysis has grown.
All body systems, including the central and peripheral nervous system, are affected by chronic renal failure and its treatment. We have developed an understanding of the long term effects of chronic hemodialysis and the physiological effects are still being studied, but some of the long term complications of chronic renal failure are still unknown. The neurological problems encountered in patients with chronic renal failure may be acute, such as dialysis disequilibrium syndrome. Dialysis disequilibrium syndrome is caused by abrupt changes in the osmotic pressure of the cerebrospinal fluid during dialysis. Chronic complications, such as uremic peripheral neuropathy and dialysis encephalopathy, also known as dialysis dementia, are also well documented. This paper will focus on one of those neurological complications of chronic renal failure namely dialysis encephalopathy.
Dialysis encephalopathy is a syndrome specific to dialysis patients that was first described by Alfrey et. al. in the early 70’s, and since then over the years many reports from other dialysis centers around the world have described similar findings. There is a characteristic set of signs and symptoms associated with dialysis encephalopathy. There is also an equal distribution among the sexes and ages, but the geographic distribution is not even.
Dialysis encephalopathy has a distinct set of characteristics. Difficulties with communication are often the presenting symptoms, followed by cognitive and motor impairment and alterations of character. Disorders of speech such as dysarthria (difficulties with articulation), dysphasia (poor speech coordination), stammering and stuttering, are characteristically the first signs of the disorder. Concomitantly, a patient often suffers with impairment of memory and depression in addition to paranoid ideas. Myoclonic jerking and seizures are also seen. Some patients have been described with dyslexia (impaired reading, writing, and spelling, without impairment in the recognition of words), dyscalculia (inability to perform mathematical problems), dyspraxia (poor performance of coordinated movements), and dysgraphia (inability to write), and worsening of attention span and a deterioration of memory are frequently seen.
Initially, these symptoms appear intermittently and infrequently, but are most noticeable immediately after dialysis. Patients are often frustrated and disturbed by these symptoms. As result, they may often curtail their conversations in order to avoid embarrassment. As the syndrome progresses, a global dementia develops and within 6 - 15 months from the onset of symptoms, the patient is usually dead.
There are characteristic EEG’s seen with this condition. Bilateral spike and wave complexes are found in the majority of patients with dialysis encephalopathy which are not usually found in other patients on dialysis. Triphasic bursts and slow, frontally predominant waves are less commonly seen. It has also been noted that there is a marked slowing of brain background rhythm in association with the bursts of spike waves. These bursts of spike waves are also seen in conjunction with normal and abnormal rhythms. It is not only possible to diagnose the condition on the basis of the EEG, it is also the principal differential diagnostic test used to confirm dialysis encephalopathy in conjunction with the characteristic alterations in the patient’s personality (Hughes 1980). A characteristic EEG is shown in Figure 1 below.
A number of histopathological changes have been seen on post mortem examinations on the brains of those with dialysis encephalopathy. However, these histopathological changes appear to be more nonspecific and more characteristic of all patients with chronic renal failure than characteristic of dialysis encephalopathy. These changes include combinations of atrophy, increased gliosis and cellular deterioration. It has been reported that some extensive neurofibrillary degeneration has been found in the cerebral cortex as well as the red nucleus and the dentato-olivary system of those with dialysis encephalopathy. In some cases, cerebral edema and herniation is also seen (Eknoyan and Knochel,1984, p.311).
Histochemical studies of those brains, however, have shown significant elevations of brain aluminum content as well as some other heavy metals. The elevated brain aluminum level is between two and three times that seen in renal patients without the encephalopathy. This finding of high concentrations of aluminum in the brains of those patients with dialysis encephalopathy suggests that this metal is the cause of the disorder. There is still some controversy regarding this metal, however, because the evidence is not conclusive, and aluminum does not fulfill all of Koch’s postulates as an etiologic agent. For instance, it is not uniformly reproducible in laboratory animals when given high doses of oral aluminum. Although elevated brain aluminum levels have also been found in patients with Alzheimer’s disease, it is also found in patients with diseases without neurological complications such as metastatic cancer and hepatic coma (Asbury, 1992). There is, however, much support for aluminum as the causative agent in dialysis encephalopathy, and some of the supporting evidence will be discussed below.
Often, especially in past years, the water used for dialysis has been modified domestic tap water. The aluminum content of domestic tap water varies according to geographical location, and some regions of the world have far greater concentrations of aluminum in their domestic water than others. Aluminum is sometimes even added to domestic water as part of the purification process. Indeed, those geographic regions with higher water aluminum concentrations also report higher incidences of dialysis encephalopathy. Indeed, the first cases of dialysis encephalopathy that were identified by Alfrey et. al. were in Denver, Colorado, which is known to have a higher than average concentration of aluminum in its domestic tap water. Aluminum in dialysis water can significantly increase blood and tissue concentrations of aluminum; it is able to cross the artificial membranes in the artificial kidneys, which are known as dialysers, and come to equilibrium between the blood and the dialysis water.
A classical example often sited in the literature is the case of the dialysis protocols in Mississippi. In Mississippi, there are marked variations in the purity of the domestic tap water across the state, and so strict programs regulating the purification of water for dialysis have been enforced. Their dialysis water is processed using a combination of charcoal and submicron filtration in addition to a reverse osmosis deionization process. Over a period of ten years, no cases of dialysis dementia were reported in Mississippi. Further, there is also a fall in the number of cases of dialysis dementia reported in those other geographic regions which have improved the purity of their dialysis water in a similar fashion. (Nissenson, Fine, and Gentile, 1984). When the dialysis bath is devoid of aluminum, there is only a removal of aluminum from the body with waste products, which can offset the gain of aluminum via ingestion.
It is difficult to avoid ingestion of aluminum because it is present in variable amounts in all foods. There may be some leaching of the aluminum from cans into prepared food, especially acidic foods such as grapefruit and mandarines. Teas and coffee also contain aluminum, which can leach out in the infusion process. Normally the gut is relatively impermeable to aluminum. Consequently, there is a very low rate of absorption in individuals with normal gastrointestinal and renal function. Normally the kidneys will also excrete the plasma aluminum in the urine. In healthy individuals, an oral dose of aluminum containing salts is associated with a rise in serum aluminum with its subsequent excretion in the urine (Wills and Savory,1989).
Aluminum salts, such as aluminum hydroxide, are frequently prescribed to patients with chronic renal failure in order to manage hyperphosphatemia. High serum phosphate levels are common and a result of the inability of the kidney to eliminate phosphate in the urine. Thus impaired phosphate excretion leads to abnormally high blood phosphate levels. Aluminum hydroxide lowers serum phosphate levels by two mechanisms. Firstly, there is adsorption of phosphate onto the surface of the aluminum hydroxide particles, and secondly, aluminum hydroxide forms aluminum phosphate in the gut from phosphate found in food. Aluminum phosphate is insoluble and therefore is not absorbed from the gut. There is an inverse relationship between serum phosphate and calcium, and high serum phosphate levels are therefore associated with pronounced bone loss (renal osteodystrophy). Phosphate binders such as aluminum hydroxide are therefore important in preventing other long term complications of renal failure. Thus, aluminum hydroxide lowers the level of soluble phosphate in the gut by the two above mentioned mechanisms and consequently, the absorption of phosphate from the gut is reduced. However, it has been proposed that this high daily intake of aluminum may precipitate the high plasma and brain phosphate levels and therefore may be the cause of dialysis encephalopathy. Much investigative work has been done on this problem.
It has been proposed that aluminum toxicity can be precipitated by some gastrointestinal disorders. It has been found that the absorption of aluminum can be enhanced by either decreasing gut motility or by decreasing the pH of the stomach. By administering citrate ion to rats with an aluminum salt, it was found that there was a significant increase in the absorption of solublized aluminum from the gut and deposition of aluminum into the tissues.
When aluminum hydroxide was given alongside citric acid (in the form of lemon juice) there were significant increases in serum aluminum levels. Another study estimated that the absorption of aluminum was 8-50 times higher in subjects that had taken aluminum-containing antacids with orange juice or citric acid, than having taken them with water. It is believed by some that the neutral aluminum citrate complex has enhanced absorption from the gut (Wills and Savory 1989).
Aluminum absorption is thought to be concentration dependent. One long- term study showed that when healthy individuals were given 5 mg or less aluminum hydroxide per day, the individuals had a negative aluminum balance. However, when doses were increased to between 1000-3000 mg/day, whole body aluminum levels were in a positive state of balance. It is thought that the upper and lower limits of the average American diet aluminum content is between 5-125 mg per day.
The site for aluminum absorption from the gut is thought to be the same as the sites for other metals such as iron, namely the duodenum or the distal jejunum. There is evidence to support two mechanisms for the absorption of aluminum from the gut into the blood. Firstly, in vitro studies using everted rat guts lead to the belief that there is an independent carrier-mediated mechanism for the absorption of Al+++, similar to the absorption of Fe+++. Iron is absorbed via the mucosal protein transferrin, which binds the iron in the lumen of the gut and transfers it across the lumenal cells into the lymphatics (Wills and Savory, 1989).
There is more evidence to suggest that the second mode of operation involving the calcium transport mechanism is the dominant mode of aluminum transport and absorption. In vitro studies using rat jejunum’s showed that calcium channel blockers inhibited the absorption of soluble aluminum. Likewise, calcium channel activators enhanced the absorption of aluminum from the gut. The calcium channel absorption theory would also explain the entrance of aluminum into the tissues. Calcium is absorbed from the gut in a two step mechanism which involves 1,25 dihydroxy-cholecalciferol, and it has been proposed that the absorption of aluminum uses the same or two similar steps. 1,25 dihydroxycholecalciferol is frequently prescribed to patients with chronic renal failure. The kidney is not only involved in the formation of urine and the regulation of water balance in the body, but it is also responsible for the synthesis of the active form of Vitamin D, 1,25-dihydroxycholecalciferol from 25-hydroxy-cholecalciferol. Studies found that vitamin D and its active metabolites increased the absorption of aluminum from the intestine and enhanced its tissue retention.
Aluminum is more difficult to remove by dialysis than other ions because it binds strongly to plasma proteins that are too large to pass through the pores of the dialyser. Furthermore, as mentioned above, aluminum incorporates itself into the tissues, brain and bone, thus making its removal difficult. Deferroxamine is a chelating agent that is used to facilitate the removal of iron and aluminum in patients with chronic renal failure and patients with acute iron poisoning, who have elevated levels of tissue heavy metals. Its most common use is in renal patients who are chronically anemic and require frequent blood transfusions. The hemoglobin is broken down, but the body is unable to eliminate the extra iron in this transfused blood and therefore the iron is deposited in the tissues. Deferroxamine, with its molecular weight of 600 g/mol is a hexadentate chelator, which can be removed from the plasma by the kidneys in patients with normal kidney function and in patients with chronic renal failure by both hemodialysis and CAPD. Following the parenteral administration of deferroxamine to patients with elevated tissue aluminum, plasma aluminum levels rise from two to four times their prior levels and are chelated by deferroxamine. Aluminum is mobilized from all tissues including the brain, to be removed from the body with deferroxamine by dialysis. Dialysis encephalopathy has been successfully stabilized using deferroxamine from over a period of several weeks, to months of treatment. It has been reported that sometimes the increased plasma levels of aluminum can enhance seizure activity in patients with dialysis encephalopathy (Schwartz, 1985).
It is believed that children are more susceptible to aluminum absorption and assimilation into the tissues than adults. Dialysis encephalopathy has not only been demonstrated in children with chronic renal failure on dialysis, but also very similar signs and symptoms have been reported in children with chronic renal failure who have not yet started hemodialysis, who however, have been taking aluminum containing phosphate binders. These children were eventually treated by parathyroidectomy in order to drop their serum phosphate levels (Geary, 1980).
Children with renal failure may be more prone to dialysis encephalopathy because their bodies are geared towards accelerated absorption of calcium for their growth requirements. Also, their needs for phosphate binders per Kg. body weight are greater than for adults. This may be related to a child’s greater energy and protein requirements. As a consequence, they also absorb and assimilate aluminum more readily than adults. In spite of attempts to reduce the exposure to aluminum in children with chronic renal failure, one study showed that elevated plasma levels of A1+++ were found in over 90 percent of pediatric renal patients in one study, both on hemodialysis and CAPD. Furthermore, there seems to be an inverse relationship between plasma aluminum levels and body weight in pediatric renal patients (De Broe and Coburn, 1990).
One alternative to hemodialysis is continuous ambulatory peritoneal dialysis (CAPD). CAPD allows the patient to continually remove waste products and toxins into fluid instilled into the peritoneal cavity. This fluid is drained out regularly every 4-8 hours and replaced with fresh solution. Some studies have shown that patients on CAPD show less hyperaluminumemia than those on hemodialysis. This may reflect a lowered need for phosphate binders as well as decreased absorption from the dialysate. With CAPD, the levels of toxins and waste products are not continually fluctuating throughout the week; rather they are continually removed from the body but at a slower rate than with hemodialysis or normal renal function.
It is not clear how aluminum acts as a toxin in dialysis encephalopathy nor how it enters and accumulates in brain tissue. In order for it to enter the brain it must cross the blood brain barrier. It appears as though there may be an increase in the permeability of the blood-brain barrier to aluminum and the subsequent buildup of the metal in brain tissue.
Once the metal has entered the brain tissue, it may alter a number of neuronal processes such as protein synthesis, axonal transport, and neurotransmitter-related events. It is known that aluminum is able to interfere with the binding of calcium ion to calmodulin. This would alter the calcium balance within the neuron and allow further influx of aluminum into the neuron. It is known that aluminum is an inhibitor of dihydropteridine reductase (DHPR), which is the enzyme responsible for the regeneration of tetrahydrobiopterin. In the brain, tetrahydrobiopterin is required for the synthesis of tyrosine, dopa, norepinephrine and 5--hydroxytryptophan (Wills and Savory).
DHPR is also found in erythrocytes, and therefore red blood cells are used as models for the function of DHPR in neural tissue. Indeed, in laboratory animals, erythrocyte DHPR activity correlates well with activity in neurons. It has also been found in the human model that neuronal DHPR activity is proportional to DHPR activity in erythrocytes. Thus, erythrocyte DHPR activity can be used as an in vivo guide to neuronal DHPR activity. In one study conducted by Altman et. al., an inverse relationship was found between the DHPR activity and plasma aluminum levels in dialysis patients. These patients had clinical evidence of dialysis encephalopathy and elevated plasma aluminum levels. Serum biopterin levels were also found to be elevated in these patients. After a single dose of deferroxamine, they found that the erythrocyte DHPR activity in these patients doubled. It was concluded that neuronal dysfunction in aluminum-toxic dialysis patients was responsible for inhibition of DHPR in the brain. Thus, the inhibition of DHPR by aluminum leads to reductions in the synthesis of monoamine neurotransmitters, leading to dialysis encephalopathy. This mechanism for the toxic effects would also explain the relationship between aluminum and Alzheimer’s disease.
Other mechanisms have been proposed to explain the association between neurotoxicity and aluminum. Cortex samples were taken from patients who had died of dialysis encephalopathy and a significant reduction was found in its content of gamma--aminobutyric acid in addition to low choline acetyltransferase activity. Homogenized cortex samples were used to study the affects of aluminum on acetylcholinesterase activity. It was found that while low levels of aluminum stimulated its activity, higher levels of aluminum significantly inhibited the activity of acetylcholinesterase. This is another mechanism which could explain the neurotoxic effects of aluminum on neuronal tissue.
In the rabbit model, choline acetyltransferase (ChAT) activity in the sciatic nerve was found to be impaired following intramedullary injections of aluminum. Kosik et. al. proposed that aluminum decreased the synthesis as well as the loading of the enzyme onto the axonal transport system.
Neurofibrillary material has been found in the cortical neurons of patients with dialysis encephalopathy. The aluminum concentration in the cytoplasm of these neurons was also found to be elevated. Scholtz and coworkers concluded that this may be evidence that aluminum has "a specific effect on neuronal protein synthesis resulting in the accumulation of neurofilaments in cortical neurons. "
Dialysis encephalopathy may not be as great of a problem in the dialysis population due to the increasing use of filtration systems in the preparation of domestic tap water used for dialysis water. The fact that dialysis encephalopathy is not seen in populations of renal patients who dialyze in units using such filtered water, but who presumably still take aluminum phosphate binders and who do not take significant precautions to limit their intake of aluminum in their diet, suggests strongly that the water used to dialyze patients is the main portal of entry of aluminum into the body. There, it distributes itself evenly in the tissues including the brain. Within the brain, it can exert its neurotoxic effects on the neurons, progressively leading to dialysis encephalopathy. Children may have enhanced absorptive mechanisms which, in addition to decreased renal function can lead to a condition analogous to dialysis encephalopathy in the population of non-dialyzing young renal renal patients. The mechanisms of entry of ingested aluminum are not yet conclusive; neither are the exact mode of neurotoxicity of aluminum.
In order to prevent dialysis encephalopathy, renal units should install filtration systems and regularly test the water for its aluminum content. This is particularly important in those geographical areas which are known to have high levels of aluminum, and where aluminum salts are used as part of the domestic tap water purification system. Children with any evidence of chronic renal failure should have their intake of aluminum strictly monitored, and care should be taken to ensure no phosphate binders are taken in association with citrate. Children should have their serum aluminum levels monitored frequently and if they are elevated, the source of aluminum should be sought. It may also be possible to limit the daily intake of phosphates and thus eliminate the need for phosphate binders. These measures should be significant in eradicating dialysis encephalopathy.
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