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0PEDIATRICS (ISSN 0031 4005). Copyright © 1986 by theAmerican Academy of Pediatrics.

Committee on Nutrition

1 150 PEDIATRICS Vol. 78 No. 6 December 1986

Aluminum Toxicity in Infants and Children0

During the last 15 years, accumulating evidence has

implicated aluminum in disorders associated withchronic renal failure.’6 The well-recognized mani-festations of systemic aluminum toxicity include

fracturing osteomalacia, dialysis encephalopathy,

and microcytic hypochromic anemia. More re-cently, aluminum loading has been demonstratedin premature infants receiving intravenous fluid

therapy.7 Although the clinical importance of thisfinding is unclear, it warrants careful attention.The association between aluminum excess and neu-rologic dysfunction, which has been reported inpatients with chronic renal failure, suggests thepossibility that aluminum overload may contribute

to the pathogenesis of CNS damage in the sickpremature infant.7’8

ALUMINUM EXPOSURE

Aluminum, which is the most abundant metal inthe earth’s crust, is ubiquitous in its distribution.7There is constant exposure to this element throughingestion of water and food and exposure to dustparticles.’0 Because aluminum sulfate (alum) is

used as a flocculating agent in the purification of

municipal water supplies, drinking water may con-tam high levels of aluminum (up to 1,000 �sg/L).

Aluminum cans, containers, and cooking utensils,as well as aluminum-containing medications, are

also potential sources of oral intake of aluminum.

Increase in aluminum intake as a result of transferthrough the skin is probably negligible; however,exposure is common due to use of aluminum indeodorants.’#{176} Some inhaled aluminum is retainedin pulmonary tissue and in the peribronchial lymphnodes, but it is largely excluded from other tissues.Pulmonary aluminum concentration increases with

age; unlike aluminum levels in other tissues, theconcentration in the lung does not correlate with

that in other tissues.Average adult intake of aluminum is probably 3

to 5 mg/d of which about 15 �g (0.3% to 0.5%) isabsorbed.1’ Most, if not all, of the absorbed alumi-

num is normally excreted in urine, leaving a total

body aluminum level at less than 30 to 40 mg.

When an individual with a normal glomerular fil-tration rate increases aluminum intake by ingestion

of aluminum-containing antacids, there is increased

absorption and urinary excretion of aluminum.’2

Although the renal handling of aluminum has not

been well defined, the normal individual appears

capable of increasing renal aluminum clearancefrom approximately 5% to about 50% of glomerular

filtration rate.’#{176}”3The low aluminum clearance nor-

mally present is largely related to the plasma bind-

ing of aluminum by a saturable plasma component

at blood levels less than 200 �.�g/L.8

Tissue aluminum levels are consistently low in

persons with normal renal function who have in-

gested large amounts of aluminum-containing ant-

acids for years.’#{176} However, in individuals with

chronic renal failure, total body aluminum can be

markedly increased. The tissues most frequently

affected and having the highest aluminum concen-

trations are bone and liver.’4

In 1976, Alfrey and associates2 published data

showing that brain tissue of patients dying from a

neurologic syndrome called dialysis encephalopathy

had high concentrations of aluminum in the graymatter. Two years later, European investigators

noted that a severe form of osteomalacic osteodys-

trophy (fracturing dialysis osteodystrophy) and di-

alysis encephalopathy occurred together in large

numbers of patients undergoing dialysis with dialy-

sate prepared from tap water that contained largeamounts of aluminum.’ The epidemic-like occur-

rence of these diseases was largely eliminated by

removing aluminum from the water used to prepare

dialysate (ie, aluminum concentration reduced to

less than 10 j�g/L).” The first reports of pediatric

patients with a progressive encephalopathy similar

to dialysis encephalopathy described children whohad not received dialysis at the time their symptoms

first appeared.’5’16 Five children with severe renal

failure secondary to congenital renal disease had aprogressive encephalopathy. They had received

doses of aluminum-containing phosphate binders

as high as 240 to 800 mg/kg/d for periods of 4 to

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AMERICAN ACADEMY OF PEDIATRICS 1151

12 months. Subsequently, from an international

� survey of pediatric dialysis facilities, 24 children

� with an unexplained form of encephalopathy were

� 0 found.8 Many of these children had not received� any form of dialysis, but all had been treated with

� aluminum-containing phosphate-binding gels.

� Since these earlier reports, both dialysis encepha-

� lopathy and aluminum-related osteomalacic osteo-

� dystrophy have been described in infants, children,

� and adults with chronic renal failure prior to initi-

� ation of dialysis.’721 The earlier reports did not

� include data on plasma and tissue aluminum levels.

� ALUMINUM-ASSOCIATED DISEASE

� In 1984, Andreoli and associates22 reported the

� occurrence of aluminum-associated bone disease in

� three infants with azotemia who did not receive

� dialysis but had been treated with aluminum hy-

droxide from the first month of life. The infants’serum aluminum levels were significantly elevated,

and biopsies of the iliac crest demonstrated severe

osteomalacia and massive deposition of aluminum

in bone. In the same year, Sedman and associates23

described a child who had chronic renal failure and

normal neurologic findings at 2 years of age and

encephalopathy when 8 years of age. This child had

not received dialysis but had received aluminum-

containing phosphate binders for 6 years. High

0 concentrations of aluminum were found in serumsamples and bone biopsy specimens. Two other

studies of children with chronic renal failure re-

ported aluminum loading in 33 children receiving

aluminum-containing antacids for control of hyper-

phosphatemia.24’2’ Serum aluminum concentrations

were increased in all instances, and bone aluminum

levels confirmed aluminum loading in five in-

stances. The oral route was assumed to be thesource of aluminum because the infused dialysate

aluminum concentration was negligible in the 23

patients receiving peritoneal dialysis and because

tap water aluminum levels were not contributoryin the seven children receiving hemodialysis. In the

data from these two studies, as well as that of

Andreoli and associates, there is a dose-dependent

correlation between elemental aluminum adminis-

tered orally to infants and children with chronic

renal failure and plasma aluminum concentra-

tions.22’24’25 Alfrey” has suggested that plasma alu-

minum levels greater than 100 to 150 ��g/L may

indicate risk for development of aluminum toxicity.

CHRONIC RENAL FAILURE

Recent studies on aluminum loading and alumi-0 num intoxication in infants and children with

chronic renal failure indicate that orally adminis-

tered aluminum-containing phosphate-binding gels

are probably the source of the excess aluminum

burden.2225 The risk of aluminum intoxication ap-

pears to be greatest in infants and small children

because of the large quantity of aluminum-contain-ing binder (per kilogram of body weight) needed tocontrol hyperphosphatemia. Adults usually con-

sume less than 30 mg/kg/d of elemental aluminum

for phosphate binding.25 In contrast, infants and

children with severe chronic renal failure have often

required aluminum at doses of 100 mg/kg/d or moreto control hyperphosphatemia and secondary hy-

perparathyroidism.’5”6’2225

A recent study26 has shown that calcium carbon-ate is as effective as aluminum hydroxide in the

control of secondary hyperparathyroidism in chil-

dren with chronic renal failure. The current rec-ommendations for the management of secondary

hyperparathyroidism in pediatric patients include

limitation of phosphorus intake, the use of calcium

carbonate as a phosphate binder, and supplemen-tation with a vitamin D metabolite or its equivalent.

Aluminum-containing phosphate binders should be

used only when the calcium binder cannot be tol-

erated or because of hypercalcemia. Because a safedosage is yet to be determined, elemental aluminum

doses should probably not exceed 30 mg/kg/d.8’25

Aluminum-free oral phosphate binders are cur-

rently being studied in Europe. These are natural

polymers consisting of heteropolyuronides charged

with calcium and iron cations.27 Iron-containingpreparations trap phosphate under acidic condi-tions, whereas, with neutral or alkaline pH, thecalcium phosphate formed is partially trapped in

the matrix of the polymer.

ALUMINUM LOADING IN INFANTS

Sedman and associates7 found high concentra-

tions of aluminum in bone, urine, and plasma ofinfants receiving intravenous therapy. Significantly

higher plasma and urinary aluminum concentra-

tions were observed in 18 premature infants admit-

ted to an intensive care unit and treated with intra-venous therapy than were found in eight term in-fants who were not given intravenous fluids. Thir-teen of the premature infants receiving intravenousfluids had a second plasma aluminum measurement

after an interval of 3 weeks while receiving formula.

Plasma aluminum concentrations for infants re-

ceiving intravenous fluid therapy were significantlyhigher than those for infants receiving formulafeeding (36.18 ± 54.57 �g/L v 8.08 ± 8.2 �zg/L). Asshown in Table 1, albumin and a number of sub-

stances frequently used as additives in the paren-

teral fluids given to premature infants have high

aluminum concentrations. (The literature contains

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1152 ALUMINUM TOXICITY

TABLE 1. Aluminum Content of Substances Commonly Added to Intravenous Solu-tions*

Additives and Solutions(Manufacturer)

No. ofLots

Tested

AluminumContent

� (�g/L)

5% Albumin (Hyland/Travenol) 7 163 ± 9625% Albumin (Hyland/Travenol) 1 448

5% Albumin (Cutter) 6 332 ± 92

25% Albumin (Cutter) 1 2,5705% Albumin (Armour) 4 1,108 ± 348

5% Albumin (Red Cross) 2 391 ± 51

25% Albumin, serum albumin 4 1,822 ± 2,503

Potassium phosphate, 3,000 mmol/L 3 16,598 ± 1,80110% Calcium gluconate 5 5,056 ± 335

Heparin, 1,000 U/mL 3 684 ± 761

5% Dextrose 2 72 ± 1

Sodium chloride, 4,000 mmol/L 3 6 ± 4

Potassium chloride, 3,000 mmol/L 1 6

* Data from Sedman et al7 and Milliner et al.’�

TABLE 2. Aluminum Content of Human Milk, Infant Formulas, Oral Glucose, andWater*

Solution No. ofLots

Tested

AluminumContent

(�g/L)

Human milk 12 9.9 ± 6.87

Glucose water 1 20

Cow’s milk-based formula20 kcal/30 mL 4 266 ± 92“Premature” (24 kcal/30 mL) 4 699 ± 321

Similac PM 60/40 (20 kcal/30 mL) 6 232 ± 60Various other Similac formulas (20 kcal 4 126-294

and 24 kcal/30 mL; Special Care)Various Enfamil formulas (20 kcal and 24 3 124-391

kcal/30 mL; “Neonatal”)Soy-based formula 4 1,478 ± 103

* Data from Sedman et al7 and Freundlich et al.’9

only scant data on the concentration of aluminum

in additives frequently used in intravenous

solutions7’28 (Table 1) and in infant feeding

mixtures7’29 (Table 2). The lack of data appears tobe a consequence of technical problems related to

the measurement of relatively low concentrations

of aluminum in an environment in which the dis-

trihution of aluminum is ubiquitous. Sedman et al7performed two-day and three-day urinary balance

studies on five infants who had been receiving

intravenous fluid therapy for at least 3 weeks. Stool

losses were reported as negligible during the balance

periods. The infants’ daily excretion of aluminum

was about 20% of that administered intravenously.

Sedman et al. also included data on bone aluminum

concentrations from autopsy specimens collected

from 23 infants, six of whom had received at least

3 weeks of parenteral nutrition. These six infants

were less than 37 weeks of gestation. Bone alumi-

num concentration was ten times higher in the sixinfants who had received at least 3 weeks of intra-

venous fluid therapy than in the 17 infants who

had received limited intravenous fluid therapy. Sed-

man and associates concluded that aluminum load-

ing occurred in premature infants as a result of the

combination of contamination of fluids given inintravenous treatment and poor renal clearance of

aluminum.The studies cited indicate that excessive alumi-

num accumulation may occur in patients with renal

failure who receive dialysis with aluminum-contam-

mated dialysate and in premature infants with re-

duced renal function given aluminum-contami-

nated intravenous fluids.17 Aluminum loading has

been observed in patients who have normal renal

function and who receive long-term parenteral nu-

trition with aluminum-contaminated fluids3032 and

in patients with chronic renal failure who ingest

aluminum-containing phosphate-binding gels.’725

Recently, Freundlich and associates29 reported two

neonates with renal failure in whom the aluminum

present in proprietary infant milk formulas ap-

peared to play a role in the development of alumi-

num toxicity. Neither infant had received oral alu-

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AMERICAN ACADEMY OF PEDIATRICS 1153

minum-containing phosphate binders or intrave-

� nous fluids. The larger infant, with a birth weight

� of 3,300 g, was treated with peritoneal dialysis from

� 0 2 weeks of age until death during the third month.� The second infant, who weighed 1,700 g at birth,

! died after 1 month of conservative management� without dialysis. Both infants received enteral au-

! mentation using a low-solute milk-based infant for-

� mula. The diagnosis of aluminum toxicity in these

! infants was based on postmortem tissue analyses.! Aluminum content of brain tissue from the larger� infant was 6.4 �sg/g in gray matter and 0.4 �g/g in

I white matter (normal < 0.1 j�g/g). Brain aluminum

� content was 47.4 /Lg/g in the smaller infant. Neither

� infant had stainable aluminum in bone or increased

� bone aluminum content. Data on the aluminum

� content of human milk and a variety of infant-

� feeding mixtures are shown in Table 2. The infants

� reported by Freundlich et a129 had been given en-

� teral alimentation using Similac PM 60/40. The

� larger infant received the ready-to-use formula; the

� smaller one received powdered formula prepared

� with sterile water. The aluminum concentrations

� in the formulas given the two infants ranged from

� 126 to 391 �zg/L. The aluminum concentration of

� the powdered milk was 232 ± 60 �tg/L and that in

� sterile water was 4 �g/L. As noted in Table 2, the

� four lots of soy formula tested by Sedman and

� associates showed higher aluminum concentrations

� 0 than the cow’s milk-based formulas (1,478 ± 103

� ��g/L).7 Although there are no data on which to base

� a firm conclusion concerning the importance of the

levels of aluminum in the soy-based infant formu-

las, it seems prudent to avoid these preparations in

low birth weight infants and others with impairedrenal function.

Deferoxamine administered intravenously has

been shown to reduce the body aluminum burdenand ameliorate injury to bone and brain in adultsreceiving hemodialysis and peritoneal dialysis.3335Andreoli and associates36 reported successful treat-ment of severe aluminum-related encephalopathyin a 7#{189}-year-old child receiving chronic peritoneal

dialysis. The deferoxamine was added to each bag

of dialysate and administered with the usual ex-

changes. Although new cases of aluminum intoxi-

cation should be preventable in most instances,deferoxamine therapy appears beneficial for thosewith established toxicity.

CONCLUSIONS

Dialysis encephalopathy and fracturing osteo-

malacia, which occurred preponderately in hemo-dialysis units using dialysis fluid contaminated with

0 aluminum, have largely disappeared since stand-

ards for safe concentrations of aluminum in dialy-

sate have been established. Infants, children, and

adults with chronic renal failure who are not re-

ceiving dialysis have been shown to be at risk foraluminum intoxication from oral administration ofaluminum-containing phosphate binders. Thiscomplication should be avoidable with the use ofphosphate binders that do not contain aluminumand the use of other measures to control hyper-

phosphatemia.

Drinking water in certain communities and someinfant formulas may contain relatively high concen-

trations of aluminum. The reported concentrationof aluminum in soy formulas is higher than in other

infant-feeding mixtures tested. These substancesmay be a significant source of aluminum in the dietoflow birth weight infants and in infants and young

children with impaired renal function.A number of substances commonly administered

intravenously, including calcium and phosphorussalts and albumin, have high levels of aluminum.

Premature infants receiving intravenous fluid ther-

apy show evidence of aluminum loading. Carefulclinical and biochemical monitoring are warranted

to determine whether it will be necessary to elimi-nate aluminum contamination of both oral and

parenteral preparations used with infants and chil-dren who may be at risk for aluminum intoxication.

COMMITTEE ON NUTRITION, 1985-1986

Laurence Finberg, MD, ChairmanHarry S. Dweck, MD

Frederick Holmes, MDNorman Kretchmer, MDAlvin M. Mauer, MD

John W. Reynolds, MDRobert M. Suskind, MD

Section Liaison

Stanley Hellerstein, MD

REFERENCES

1. Alfrey AC, Mishell JM, Burks J, et al: Syndrome of dys-praxia and multifocal seizures associated with chronic he-modialysis. Trans Am Soc Artif Intern Organs 1972;18:257-261

2. Alfrey AC, LeGendre GR, Kaehny WD: The dialysis en-cephalopathy syndrome: Possible aluminum intoxication. NEngI J Med 1976;294:184-188

3. Ward MK, Feest TG, Ellis HA, et al: Osteomalacic dialysisosteodystrophy: Evidence for a water-borne aetiologicalagent, probably aluminum. Lancet 1978;1:841-845

4. Dewberry FL, McKinney TD, Stone WJ: The dialysis de-mentia syndrome: Report of fourteen cases and review ofthe literature. Trans Am Soc Artiflntern Organs 1980;3:102-107

5. Mehta RP: Encephalopathy in chronic renal failure appear-

ing before the start of dialysis. Can Med Assoc J1979;120:1112-1114

6. O’Hare JA, Murnaghan DJ: Reversal of aluminum-induced

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1154 ALUMINUM TOXICITY

hemodialysis anemia by a low-aluminum dialysate. N EngiJ Med 1982;306:654-656

7. Sedman AB, Klein GL, Merritt RJ, et al: Evidence ofaluminum loading in infants receiving intravenous therapy.N Engl J Med 1985;312:1337-1343

8. Polinsky MS, Gruskin AB: Aluminum toxicity in childrenwith chronic renal failure. J Pediatr 1984;105:758-761

9. Epstein SG: Aluminum in nature, in the body and its rela-tionship to human health. Trace Subst Environ Health1984;18:139-148

10. Alfrey AC: Aluminum. Adv Clin Chem 1983;23:69-911 1. Alfrey AC: Aluminum intoxication, editorial. N Engi J Med

1984;310:1113-111512. Kaehny WD, Hegg AP, Alfrey AC: Gastrointestinal absorp-

tion of aluminum from aluminum-containing actacids. NEngI J Med 1977;296:1389-1390

13. Polinsky MS, Gruskin AB, Baluarte HJ, et al: Aluminum inchronic renal disease, in Strauss J (ed): Pediatric Nephrol-ogy. New York, Plenum Press 1981, vol 6, p 315

14. Alfrey AC, Hegg A, Craswell P: Metabolism and toxicity of

aluminum in renal failure. Am J Clin Nutr 1980;33:1509-1516

15. Baluarte HJ, Gruskin AB, Hiner LB, et al: Encephalopathy

in children with chronic renal failure. Proc Clin Dial Travis-plant Forum 1977;7:95-98

16. Foley CM, Polinsky MS, Gruskin AB, et al: Encephalopathyin infants and children with chronic renal disease. ArchNeurol 1981;38:656-658

17. Nathan E, Pederson SE: Dialysis encephalopathy in a non-

dialysed uraemic boy treated with aluminum hydroxide or-ally. Acta Paediatr Scand 1980;69:793-796

18. Felsenfeld AJ, Gutman RA, Llach F, et al: Osteomalacia inchronic renal failure: A syndrome previously reported onlywith maintenance dialysis. Am J Nephrol 1982;2:147-154

19. Griswold WR, Reznik V, Mendoza SA, et al: Accumulationof aluminum in a nondialyzed uremic child receiving alu-minum hydroxide. Pediatrics 1983;71:56-58

20. Randall ME: Aluminum toxicity in an infant not on dialysis,letter.Lancet 1983;1:1327-1328

21. Kaye M: Oral aluminum toxicity in a non-dialyzed patientwith renal failure. Clin Nephrol 1983;20:208-211

22. Andreoli SP, Bergstein JM, Sherrard DJ: Aluminum intox-ication from aluminum-containing phosphate binders inchildren with azotemia not undergoing dialysis. N EngI JMed 1984;310:1079-1084

23. Sednian AB, Wilkening GN, Warady BA, et al: Encephalop-

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24. Salusky IB, Coburn JW, Paunier L, et al: Role of aluminumhydroxide in raising serum aluminum levels in childrenundergoing continuous ambulatory peritoneal dialysis. JPediatr 1984;105:717-720

25. Sedman AB, Miller NL, Warady BA, et al: Aluminum load-ing in children with chronic renal failure. Kidney mt1984;26:201-204

26. Mak RHK, Turner C, Thompson T, et al: Suppression ofsecondary hyperparathyroidism in children with chronic

renal failure by high dose phosphate binders: Calcium car-bonate versus aluminum hydroxide. Br Med J 1985;291:623-

62727. Schneider H, Kulbe KD, Weber H, et al: Aluminum-free

oral phosphate binder. Clin Nephrol 1985;24(suppl):S-98

28. Milliner DS, Shinaberger JH, Shuman P, et al: Inadvertent

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29. Freundlich M, Zilleruelo G, Abitbol C, et al: Infant formulaas a cause of aluminum toxicity in neonatal uraemia. Lancet1985;2:527-529

30. Klein GL, Ott SM, Alfrey AC, et a!: Aluminum as a factorin the bone disease of long-term parenteral nutrition. TransAssoc Am Physicians 1982;95:155-164

31. Klein GL, Alfrey AC, Miller NL, et al: Aluminum loadingduring total parenteral nutrition. Am J Clin Nutr1982;35:1425-1429

32. Ott SM, Maloney NA, Klein GL, et al: Aluminum is asso-ciated with low bone formation in patients receiving chronicparenteral nutrition. Ann Intern Med 1983;98:910-914

33. Ackrill P, Ralston AJ, Day JP, et al: Successful removal ofaluminum from patient with dialysis encephalopathy, letter.Lancet 1980;2:692-693

34. Malluche HH, Smith AJ, Abreo K, et al: The use of defer-oxamine in the management of aluminum accumulation inbone in patients with renal failure. N Engl J Med1984;311:140-144

35. Ackrill P, Day JP: Desferrioxamine in the treatment ofaluminum overload. Clin Nephrol 1985;24(suppl):S-94

36. Andreoli SP, Dunn D, DeMyer W, et al: Intraperitonealdeferoxamine therapy for aluminum intoxication in a childundergoing continuous ambulatory peritoneal dialysis. JPediatr 1985;107:760-763

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