Dementia in Patients Undergoing Long-Term Dialysis

Dementia in Patients UndergoingLong-Term DialysisAetiology, Differential Diagnoses, Epidemiology and Management

Peter Maria Rob,1 Colmar Niederstadt2 and Erich Reusche3

1 Nephrologisches Zentrum am Klinikum Süd, Lübeck, Germany2 Nephrologisches Zentrum Niedersachsen, Hann. Münden, Germany3 Department of Pathology/Neuropathology, Universitätsklinikum Lübeck, Lübeck, Germany

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6911. Dementias in Dialysis Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692

1.1 Uraemic Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6921.2 Dialysis Encephalopathy Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6921.3 Dialysis-Associated Dementia/Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . 6931.4 Role of Aluminium in the Pathogenesis of Dementias . . . . . . . . . . . . . . . . . . . . . . . 694

1.4.1 Neurotoxicity of Aluminium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6942. Diagnosis and Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6953. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6954. Therapeutic Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6965. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697

Abstract Dementia in patients undergoing long-term dialysis has not been clearlydefined; however, four different entities have been described.

Uraemic encephalopathy is a complication of uraemia and responds wellto dialysis.

Dialysis encephalopathy syndrome, the result of acute intoxication of alumin-ium caused by the use of an aluminium-containing dialysate, was a commonoccurrence prior to 1980. However, using modern techniques of water purifica-tion, such acute intoxication can now be avoided.

Dialysis-associated encephalopathy/dementia (DAE) is always associatedwith elevated serum aluminium levels. Pathognomonic morphological changesin the brain have been described, but the mechanism for the entry of aluminiuminto the CNS is incompletely understood. The mechanisms involved in thepathogenesis of the neurotoxicity associated with aluminium are numerous.Although only a very small fraction of ingested aluminium is absorbed, the con-tinuous oral aluminium intake from aluminium-based phosphate binders, andalso of dietary or environmental origin, is responsible for aluminium overloadin dialysis patients.

Age-related dementia, especially vascular dementia, occurs in patients under-going long-term dialysis as frequently as it does in the general population.

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The differential diagnoses of dialysis-associated dementias should includeinvestigation for metabolic encephalopathies, heavy metal or trace element in-toxications, and distinct structural neurological lesions such as subdural haema-toma, normal pressure hydrocephalus, stroke and, particularly, hypertensiveencephalopathy and multi-infarct dementia.

To prevent DAE, dietary training programmes should aim to achieve the low-est phosphate intake and pharmacological tools should be used to keep serumphosphate levels below 2 mmol/L. To prevent vascular dementia, lifestyle modifi-cation should be undertaken, including optimal physical activity and fat intake,nicotine abstinence, and targeting optimal blood glucose, cholesterol and triglyceridelevels, and blood pressure, to those outlined in current recommendations.

Dementia is a syndrome associated with chronicdisease of the brain that affects multiple corticalfunctions including memory, thinking, orientation,attention, speech, calculation, and the managementof ideas and abstractions. These deficiencies are of-ten accompanied by alterations of emotional controland social behaviour.

In the general population the incidence and prev-alence of dementia increases with age.[1] Dementiaof the Alzheimer’s type is the main contributor to thesteep increase in prevalence with age, whereas theprevalence of vascular dementia increases graduallyover various age groups.[2]

In patients with end-stage kidney disease, long-term dialysis therapy has resulted in an improve-ment in the duration and quality of life. The charac-teristics of patients undergoing dialysis has changedremarkably during the last decade: there has beenan increase in mean age and in the proportion ofpatients with type 2 (non–insulin-dependent) di-abetes mellitus. Patients undergoing dialysis candevelop dementia of a number of types, each ofwhich requires specific treatment. Vascular demen-tia and dementia of the Alzheimer’s type occur inpatients with end-stage kidney failure as frequentlyas they do in the general population. The epidemi-ology and prevention/treatment of Alzheimer’s dis-ease dementia will not be discussed in this article.

1. Dementias in Dialysis Patients

1.1 Uraemic Encephalopathy

The term ‘uraemic encephalopathy’ is used to

describe the nonspecific neurological symptoms ofuraemia which respond to dialysis treatment.

Uraemic encephalopathy is an acute or subacuteorganic brain syndrome that occurs frequently incases of accumulation of unknown uraemic toxinsin patients with advanced renal failure. The patientsdisplay neuropsychiatric symptoms, including dis-orders of consciousness, psychomotor behaviour,thinking, memory, speech, perception and emo-tion.[3]

Uraemic encephalopathy can be treated effec-tively with dialysis, and the symptoms are usuallyrelieved almost entirely. Dialysis is initiated now-adays in most cases early enough to prevent theoccurrence of uraemic encephalopathy.

After initiation of dialysis, other neuropsych-iatric abnormalities may occur which can be dis-tinguished from uraemic encephalopathy. Theytend to appear later on in chronic renal failure anddo not usually respond to the dialysis procedure.These are described in sections 1.2 and 1.3.

1.2 Dialysis Encephalopathy Syndrome

‘Dialysis dementia’, or the ‘dialysis encephalo-pathy syndrome’ (DES), is a disease related to anacute intoxication of aluminium caused by the useof an aluminium-containing dialysate.[4] The clin-ical signs are dyspraxia, dysarthria, trembling, my-oclonus, ataxia, convulsions and emotional alter-ations. Postmortem, a high aluminium level isalways found in the brain.

Before the introduction, in 1980, of deferoxamine(desferrioxamine) as an aluminium chelating agent,

692 Rob et al.

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DES was almost invariably fatal.[5] Nowadays, usingmodern techniques of water purification this acutedisease can be avoided.

1.3 Dialysis-AssociatedDementia/Encephalopathy

Dialysis-associated dementia or encephalopathy(DAE) is the result of long-term ingestion of alu-minium-containing drugs, food and beverages.[6,7]

The clinical picture of this form of dementia is thesame as that of age-related forms of dementia.

There is evidence that continuous aluminiumintake occurs in dialysis patients, due to the useof aluminium-based phosphate binders. Theseagents are frequently used in end-stage renal fail-ure to control hyperphosphataemia since they areinexpensive and very effective. Aluminium is de-posited in the brain and causes an chronic enceph-alopathy. The syndrome is always associated withelevated serum aluminium levels.[8] High alumin-ium levels have also been found in the bone of 30%of dialysis patients.[9] There is a significant posi-tive correlation between renal osteodystrophyand serum aluminium level.[10] In peripheral or-gans, the intensity of aluminium deposition cor-relates with the intake of aluminium-based phos-phate binders.[11] In addition, it was shown that anincreased aluminium burden has an adverse effecton overall mortality in patients undergoing dial-ysis.[9]

Since the report of Alfrey et al.[4] in 1976 in fatalcases of DES, only nonspecific pathological changeshave been shown in the CNS.[12] In 1991, we des-cribed pathognomonic morphological changesin a postmortem study of patients who had under-gone long-term haemodialysis. Typical argyro-philic, aluminium-containing deposits were dem-onstrated.[13,14] Due to long-term processes oflysosomal digestion, aluminium-induced degrada-tion products were found exclusively in the cyto-plasm of the choroid plexus epithelia (‘kidney ofthe brain’), cortical/subcortical glia and numerousneuronal populations.[15] Increased levels of alu-minium have been demonstrated in subcellularstructures of neurons and glia by laser microprobe

mass analysis. This type of aluminium depositionis the morphological basis of DAE, and is notfound in the acute and often lethal DES describedin section 1.2. Additionally, it was shown clinicallythat the intake of aluminium-based phosphatebinders correlates significantly with the intensityof aluminium deposition in central and peripheralorgans.[11]

Although there are some unresolved questions,most cases of DES and even DAE have been associ-ated with high levels of aluminium in the dialysateor the long-term intake of aluminium-containingphosphate binders or aluminium-containing ant-acids. In some sporadic cases the excess alumin-ium found in the brain may have been the resultof ‘dietary’ intake, which is typically 10 to 100mgdaily.[16] Only a very small fraction of this amountis absorbed, but enteral aluminium uptake may beincreased in individuals with renal failure. Themechanism is not clearly understood; however, inrats, administration of parathyroid hormone (PTH),in the absence of renal failure, induced increasedenteral aluminium absorption and increased de-position of aluminium in the brain.[17] In most pa-tients with renal failure, PTH levels are elevateddue to secondary hyperparathyroidism. However,in patients undergoing haemodialysis, high plasmalevels of PTH were not associated with enhancedintestinal absorption of aluminium.[18] Other investi-gators found increased aluminium absorption inuraemic patients taking vitamin D3.[19]

One of the unresolved questions is, how alumin-ium enters the brain in increased quantities. It isnot clear by which pathway aluminium crosses theblood-brain barrier (BBB). There is little free alu-minium in the blood, since most of it is bound totransferrin.[20] In CSF, it may be bound to citrate orsilicate.[21] The uptake of aluminium at the BBB ismediated by transferrin receptors;[22] however, theBBB in patients who have undergone long-termdialysis may be impaired[23-25] and, therefore, eventransferrin-bound aluminium may enter the brain.Any free aluminium in blood can readily enterthe CNS.

Dialysis-Associated Encephalopathy 693


Elevated brain aluminium levels are also seen inmany other groups of patients, including thosewith hepatic encephalopathy who are over 60 yearsof age and those with Alzheimer’s disease, althoughthey are generally lower than those observed inpatients with DAE.[26] There is no obvious thresh-old level for brain aluminium that determinestoxicity. In general though, levels above 15 μg/kgof dry weight are often associated with the enceph-alopathy, while levels below 5 μg/kg are not.

1.4. Role of Aluminium in the Pathogenesisof Dementias

Neurofibrillary changes similar to those seenin Alzheimer’s disease have been experimentallyproduced by the administration of aluminiumto a number of different animal species.[26] Theintroduction of haemodialysis was followed byepidemics of lethal DES caused by aluminium-contaminated dialysis fluids. These data gave riseto the speculation that the morphological alter-ations associated with Alzheimer’s disease mayin fact be linked to aluminium metabolism. Thisfield remains controversial, having both its sup-porters[27] and its opponents.[28]

In particular, controversial epidemiological re-sults have been obtained from a number of studiesaddressing the problem of aluminium in drinkingwater. In the 1960s and 1970s, non–aluminium-depleted drinking water was used for dialysateproduction and caused DES.[29] Both a positivecorrelation[30-32] and no correlation[33,34] have beenfound between the aluminium content in drink-ing water and Alzheimer’s disease. Interestingly,Martyn et al.[35] reported a correlation between theincidence of Alzheimer’s disease and the alumin-ium content of drinking water. However, the samegroup published a subsequent paper in which theyconcluded that ‘there was little association be-tween AD [Alzheimer’s disease] and higher alu-minium or lower silicon levels in drinking waterwhen cases were compared with any of the controlgroups’.[36]

We have found in a group of 127 long-termdialysis patients only a single patient showing a

mixture of neurofibrillary changes of the Alzheimer-type and deposits of the DAE type.[37] Both morpho-logical types of alterations were intermingled.[37]

Additionally, one case of undiagnosed DAE pre-sented distinct age-related βA4-amyloid deposi-tions of the Alzheimer-type.[38] In a study of 50long-term dialysis patients, we found a correlationbetween the amount of drug-related aluminium in-take and the degree of DAE-related morphologicalchanges.[11] In long-term dialysis patients under60 years of age, no Alzheimer-related changes wereseen despite a history of ingestion of up to 2.5kgof aluminium over a period of several years (un-published observations). Patients over 60 years ofage occasionally presented with sparse depositsof βA4-amyloid and/or a low incidence of neuro-fibrillary tangles of the Alzheimer- type. In accord-ance with the criteria of the Consortium to Establisha Registry for Alzheimer’s Disease (CERAD), thesewere identified as normal, age-related phenomena(unpublished observations).

In summary, our morphological and epidemio-logical data suggest that aluminium does not causean increase in AD-like morphology in long-termdialysis patients.

1.4.1 Neurotoxicity of AluminiumThe question of why aluminium is neurotoxic

has not been clearly answered. Some mechanismsare possibly involved and have been discussed inthe literature. Aluminium interferes with voltage-dependent ion channels which may be a cause ofthe aluminium-dependent increase in BBB perme-ability.[39] Aluminium inhibits cholinergic neuro-transmission, related to an enhanced availability ofacetylcholine.[40] Aluminium also inhibits dihydro-biopterin reductase, resulting in downstream accu-mulation of phenylalanine.[41] The clinical signs ofphenylalanine accumulation are seizures, progres-sive cerebral and basal ganglia dysfunction result-ing in rigidity, chorea, spasms and muscle hypoto-nia. Antidopaminergic effects of aluminium havebeen described.[42] It also seems to promote the ag-gregation of β-amyloid peptide.[43] And last but notleast, aluminium has been shown to potentiateoxidative stress.[44,45]

694 Rob et al.


2. Diagnosis and Differential Diagnoses

What other factors may play a role in the dev-elopment of dementia in patients with long-termrenal failure? In general terms, there are numerouscauses of dementia, but in patients undergoinglong-term dialysis, dementia remains rare.

DAE must be differentiated from metabolicencephalopathies such as hypercalcaemia, hypo-glycaemia, hyperosmolarity, hyponatraemia andhyperparathyroidism, as well drug intoxications.Heavy metal or trace element intoxications, suchas stannium (tin hydrate) or strontium, also haveto be considered.[46] Distinct structural neurologicallesions, such as subdural haematoma, normal pres-sure hydrocephalus and stroke, and, particularly,hypertensive encephalopathy and multi-infarctdementia, have to be excluded (table I).

3. Epidemiology

The incidence and prevalence data of dementiain the general population show little geographicalvariation and an increase with age. The age-stand-ardised prevalence is 6.4% for dementia of allcauses, 4.4% for Alzheimer’s disease dementia,and 1.6% for vascular dementia.[1,2] The epidemi-ology of DAE is unknown for several reasons. TheICD-10 classification of diseases does not containthe specific subgroup of DAE.[47] The clinical fea-tures of DAE include depression, myoclonus, sei-zures, drop attacks and extrapyramidal symptoms,which are often related to ischaemic brain diseasebut not to the amount of aluminium intake.[38]

Clinically, DAE cannot be clearly differentiatedfrom other chronic brain diseases leading to de-mentia. As the population of dialysis patients isgetting older, other reasons for age-associateddementia become more prevalent. The increasingprevalence of diabetes mellitus among long-termdialysis patients may substantially increase therisk of dementia among such patients due to morefrequent subcortical arteriosclerotic encephalo-pathy in patients with diabetes.[48]

The differentiation between Alzheimer’s diseaseand vascular dementia is no longer very clear.[49]

Table I. Causes of dementia

Primary cerebral cortical degenerations

Alzheimer’s disease

Pick’s disease

Diffuse Lewy body disease

Cerebrovascular disease

Multi-infarct dementia

Hypertensive encephalopathy

Binswanger’s disease

Cranial arteritis

Other cranial angiitis

Ischaemia of various origin

Primary subcortical degeneration

Parkinson’s disease

Multiple system atrophy

Huntington’s disease

Progressive supranuclear palsy

Cerebral infections and inflammations

Neurosyphilis

Post-encephalitis

Paraneoplastic encephalitis

Progressive multifocal leucencephalopathy

Multiple sclerosis

Acquired immunodeficiency syndrome

Prion diseases

Creutzfeldt-Jakob disease

Kuru

Toxic and metabolic causes

Alcohol

Drugs (e.g. levodopa)

Hypothyroidism

Hypercalcaemia

Hepatic encephalopathy

Uraemia and dialysis-associated encephalopathy

Vitamin B12 deficiency

Hyperparathyroidism

Chronic hyperosmolarity

Tumours and hydrocephalus

Primary intracranial tumours

Secondary deposits

Aqueductal stenosis

Communicating hydrocephalus

Brain injury

Diffuse or focal brain injury

Subdural haematoma

Dementia pugilistica



Vascular dementia is considered to be a heteroge-nous group of syndromes, and there is a lack of con-sensus on the appropriate diagnostic criteria.[50]

The diagnosis of mixed dementia in patients withvascular impairment was the focus of a recentpaper.[51] The authors suggest an operational def-inition based on clinical and radiographic find-ings, but one that is indifferent to vascular riskfactors. Thus, one has to consider both the alu-minium-induced DAE and the vascular dementiain long-term dialysis patients with signs of de-mentia.

Given the difficulty in clearly defining DAE,it is not surprising that there are few data address-ing its epidemiology. The prevalence of DAE inEurope has been reported to be between 0.6[52] and4%.[11] However a higher prevalence has also beenreported; among more than 12 000 patients, 30%showed clinical symptoms of aluminium overload,49% had high baseline serum aluminium levelsand 55% an increase in serum aluminium levelsafter deferoxamine infusion.[46] Still other papersaddressing long-term problems in dialysis pa-tients do not mention DAE, suggesting that it is arare phenomenon and/or that nephrologists do notpay enough attention to this problem.[53-55]

4. Therapeutic Options

The elimination of aluminium by deferoxaminefollowed by dialysis improves the mental functionof dialysis patients. Compared with a control groupwith similar IQ, dialysis patients with only mildlyelevated plasma aluminium levels showed abnor-malities in a variety of psychomotor functions.[56]

After treatment with deferoxamine, plasma alumin-ium levels were lowered and the erythrocyte activ-ity of dihydropteridine reductase doubled, an effectthat was significantly correlated with changes inpsychomotor performance.[56] Thus, aluminium mayexert a specific toxic effect in patients with chronicrenal failure.

The necessity of prescribing aluminium-basedphosphate binders should be minimised by opti-mal and individual dietary training programmesand high quality dialysis. Patients should develop

a knowledge of the phosphate content of variousfoods and should ensure that they ingest no morethan 2000mg of phosphate per day. Serum phos-phate levels should be checked monthly and keptbelow 2 mmol/L. If the serum phosphate level isabove 2 mmol/L, the dietary training programmeshould be repeated and attempts made to motivatethe patient to take responsibility for the preventionof encephalopathy (and osteopathy).

The daily use of calcitriol should be stoppedin order to minimise the enteral phosphate uptake;instead calcitriol should be administered intrave-nously 2 or 3 times per week.[46] If the av-fistula,the dialysis dosage and the dialyser are optimal, thefirst-line treatment is calcium-based phosphatebinders, such as calcium acetate or calcium carbo-nate, to be taken with a meal. The dosage may beincreased until hypercalcaemia appears. A low-calcium dialysate may be used to treat hypercal-caemia. If the serum phosphate level remains above2 mmol/L, the novel phosphate binder sevelamer,[57]

which is as effective as calcium acetate,[58] maybe tried.

The use of essential amino acids to increase themetabolic use of phosphate by an anabolic effecthas been suggested[59,60] but is rather expensiveand less effective in our personal opinion. If otherapproaches are unsuccessful, aluminium-basedphosphate binders should be prescribed as a lastresort. Because aluminium hydroxide has to be ac-tivated to aluminium chloride by gastric acid, theuse of aluminium chloride itself is recommended.Since gastric acid production is often impaired inpatients undergoing long-term dialysis, aluminiumchloride should be given during each phosphate-containing meal. Patients have to be instructed toavoid additional aluminium intake [reduce theirintake of baking powder, avoid cooking with orkeeping acidic foods (e.g. tomatoes) in aluminium-containing vessels], or to avoid taking other alu-minium-containing drugs such as some free avail-able acid binders.[46] Low iron status has to bestrictly avoided since it increases the availability offree binding sites for aluminium at its transportprotein transferrin.

696 Rob et al.


Physicians should control dialysate aluminiumlevels twice yearly. Aluminium levels in the dialy-sate must be below 5 μg/L, but one should aim toachieve levels below 2 μg/L. In the serum, alumin-ium levels should be below 20 μg/L. If the serumaluminium level is above 30 μg/L, a deferoxamineinfusion (5 mg/kg bodyweight) should be given 5hours prior to the start of haemodialysis.[61] Aserum aluminium increment after deferoxamine of30 μg/L has a sensitivity of 91% for detecting alu-minium overload.[62] However, in patients with hyp-erparathyroidism the test has low specificity.

An increased risk of aluminium toxicity is pre-sent in patients in whom a serum aluminium incre-ment >30 μg/L is accompanied by a serum intactPTH level of between 150 and 650 ng/L. However, itshould be noted that these ranges have been vali-dated for aluminium bone disease and not for DAE.The aluminium-deferoxamine complex is watersoluble and can easily be eliminated via dialysisusing a high-flux membrane.

Allergic, gastric, neurological, ophthalmologicaland other adverse effects to deferoxamine have tobe considered, and iron status, which can be reducedby the drug, has to controlled regularly.[63,64]

Finally, doctors have to focus on secondaryprevention of vascular risk factors because of theincreasing age of dialysis patients and the increas-ing prevalence and incidence of dementia withaging, especially that due to vascular processes. Inbrief, this involves aiming for the best glycosylatedhaemoglobin level (<7.5%), an optimal blood pres-sure (130/85mm Hg), the treatment of hyperlipid-aemia, the lowering of hyperhomocystinaemia bymeans of vitamin B12 and folate, the avoidance ortreatment of hyperparathyroidism, choosing theoptimal individual dialysis prescription, and, espe-cially, an optimal calcium : magnesium ratio.[65]

Due to its well known arteriosclerosis-promotingeffects, smoking should be avoided in patientsundergoing long-term dialysis, although, confus-ingly, there are recent data demonstrating thesuccessful use of pure nicotine derivatives indementia.[66]

5. Conclusions

Dementia in patients undergoing long-termdialysis is as frequent as dementia in the generalpopulation. Uraemic encephalopathy occurs inpatients with advanced renal failure resulting fromthe accumulating uraemic toxins and responds tothe dialysis procedure. DES was a disease relatedto an acute intoxication of aluminium due to poorwater purification which nowadays can easily beavoided using modern water purification tech-niques. DAE is the result of long-term oral intakeof aluminium-containing drugs, food and beverages.Dietary training programmes should aim toachieve the lowest phosphate intake possible, andpharmacological tools should be used to keep serumphosphate level below 2 mmol/L. Because of theincreasing incidence of vascular dementia in theelderly, doctors have to focus on secondary pre-vention of vascular risk factors.

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Correspondence and offprints: Prof. Peter Maria Rob,Nephrologisches Zentrum am Klinikum Süd Kalhlhorststr.31, D-23552, Lübeck, Germany.E-mail: [email protected]



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Dementia in Patients Undergoing Long-Term Dialysis