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CLINICAL STUDY
Aluminum overload in the reverse osmosis dialysis era: does it exist?
Mei-Yin Chen
a,b
, Shih-Hsiang Ou
c,d
, Nai-Ching Chen
e
, Chun-Hao Yin
f
and Chien-Liang Chen
c,d,f,g,h
a
Department of Nutrition and Food Service, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;
b
Department of Nursing, Shu-
Zen Junior College of Medicine and Management, Kaohsiung, Taiwan;
c
Division of Nephrology, Kaohsiung Veterans General Hospital,
Kaohsiung, Taiwan;
d
Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taiwan;
e
Department of
Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;
f
Division
of Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;
g
Institutes of Clinical Medicine, National Yang
Ming Chiao Tung University, Taiwan;
h
Institution of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
ABSTRACT
Background: Aluminum accumulation is a well-described complication in dialysis patients.
Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum
overload. Limited evidence suggests that aluminum overload may decline in the era of alumi-
num removal from dialysis fluids, even with the use of aluminum binders.
Methods: We examined the data from January 2014 to June 1, 2020, identified through our elec-
tronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The
presentation and treatment of aluminum overload were recorded.
Results: Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients
(47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients
had symptoms, including one patient with an unexplained fracture, eight patients with unex-
plained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with
hypercalcemia (serum calcium >11 mg dL
-1
). None of the patients with aluminum overload
developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requir-
ing longer treatments (>10 months versus <10 months) had similar basal serum aluminum
(p¼0.219) but had an increase in serum aluminum after DFO (p¼0.041). Furthermore, the treat-
ments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline
phosphatase levels <60 U L
-1
(p¼0.028).
Conclusion: We concluded that aluminum overload existed in the reverse osmosis dialysis era.
In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum
in dialysis patients should be monitored in countries using aluminum-based phosphate binders,
despite reverse osmosis dialysis.
ARTICLE HISTORY
Received 30 March 2022
Revised 6 July 2022
Accepted 13 July 2022
KEYWORDS
Aluminum; aluminum
overload; desferrox-
ime; dialysis
Introduction
Patients with chronic kidney disease are at a high risk
of aluminum overload due to poor renal excretion of
aluminum [1]. It has been suggested that dialysis cen-
ters should serially follow serum aluminum levels as a
screening tool for patients at risk of aluminum toxicity
[2–4]. Aluminum can be eliminated from the dialysate
using reverse osmosis techniques. Improvements in
hemodialysis technology and patient care may have
eliminated the occurrence of aluminum overload. The
low prevalence of aluminum toxicity among dialysis
patients has raised a debate about the need to con-
tinue screening for aluminum overload in dialysis
patients [5,6], which the Kidney Disease Outcomes
Quality Initiative (K/DOQI) guidelines suggest routinely
[2]. Aluminum-containing phosphate binders are an
important source of aluminum exposure in dialysis
patients. Although aluminum-based phosphate binders
used as short-term therapy are considered by the K/
DOQI guidelines, some patients with hyperphosphate-
mia under calcium-based phosphate binders compli-
cated by hypercalcemia still extend the duration of
aluminum therapy. The Dialysis Outcomes and Practice
Patterns Survey 2011 report found 12.7% and 13.7%
usage of aluminum binders in Spain and Australia,
respectively, but 0%, 0.1%, and 0.3% in Belgium, the
United States, and Japan, respectively [7]. Sevelamer
hydrochloride and lanthanum carbonate have been
CONTACT Chien-Liang Chen cclchen@seed.net.tw Division of Nephrology, Kaohsiung Veterans General Hospital, Taiwan, 386 Ta-Chung 1st Rd,
Kaohsiung City, Taiwan
ß2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
RENAL FAILURE
2022, VOL. 44, NO. 1, 1596–1604
https://doi.org/10.1080/0886022X.2022.2104165
suggested as non-calcium and non-aluminum phos-
phate binders, respectively. However, these newly
developed medications have not become popular
because of their high costs. Some experts believe that
aluminum-based phosphate binders continue to play a
role in clinical nephrology practice [8]. Indeed, there are
several other possible sources of aluminum besides
phosphate binders because aluminum salts are used in
water treatment, bakery products, and pharmacy proc-
esses. Aluminum containers, utensils, and cookware
may cause aluminum to migrate from the instrument
into the solution [9–11]. Therefore, aluminum overload
in the reverse osmosis dialysis era remains
controversial.
Excess aluminum may cause dialysis dementia,
erythropoietin-resistant microcytic anemia, or bone dis-
ease [12]. Patients with aluminum-related bone diseases
may experience muscle weakness, musculoskeletal
pain, or fractures. Aluminum overload and other com-
plications can develop in patients on dialysis, especially
during parathyroidectomy (PTX) [13]. Patients may have
hypercalcemia due to aluminum blocking the additional
calcium uptake into the bone from the additional cal-
cium in the calcium phosphate binder with intensive
vitamin D treatment or the high calcium content dialy-
sis fluid superimposed by a decrease in bone turnover
during anti-resorption therapy or hypoparathyroidism
after PTX [12,14,15]. An early diagnosis of aluminum
toxicity is important to ensure effective therapy. Bone
biopsy specimens are considered the gold standard for
diagnosing aluminum overload in dialysis patients
[2,15,16]. In the absence of a bone biopsy, diagnosis
can be made by measuring serum aluminum levels
before and after a noninvasive deferoxamine (DFO) test
to identify subjects with an increased body burden of
aluminum [2,17–19]. DFO tests should be performed if
there are elevated serum aluminum levels (60 200 mg
L
-1
) or clinical signs and symptoms of aluminum tox-
icity, or before PTX if the patient has been exposed to
aluminum for at least four months [2].
The improvements in hemodialysis technology and
restrictions on the use of aluminum-based phosphate
binders have resulted in a low prevalence of aluminum
toxicity (2%) among hemodialysis patients in the
United States [4–6]. However, there is 25% of aluminum
bone diseases [20], 16.2% of aluminum overload in
patients at an Iran dialysis center [21], and 8% of alumi-
num overload in Taiwan [22]. The diversity of the alumi-
num reports may be due to the different country
circumstances, dialysis care and definition of aluminum
overload in bone biopsy, single serum aluminum or a
positive DFO test.
The clinical presentation and incidence of aluminum
overload in the reverse osmosis dialysis era with the
permitted use of aluminum-based phosphate binders
remain unknown. We examined data from the
Kaohsiung Veterans General Hospital dialysis clinic to
evaluate serum aluminum levels and the DFO test for
aluminum overload. The incidence, clinical presenta-
tion, and treatment of aluminum overload were
also analyzed.
Materials and methods
Design
This retrospective study evaluated noninvasive test
strategies for predicting aluminum overload in a group
of dialysis patients. There is a standard treatment proto-
col for hyperphosphatemia in dialysis patients. Most of
the patients are prescribed calcium-based phosphate
binders, but when serum phosphate levels exceed
6.0 mg dL
-1
or the product of serum calcium x serum
phosphate exceed 55 mg
2
dL
-2
, aluminum hydroxide
324 mg tablets are prescribed 1# to 4# three times a
day. These test parameters were evaluated against the
pathological diagnosis of aluminum overload based on
the deferoxamine test (‘gold standard’). The study was
conducted in accordance with the Declaration of
Helsinki and the protocol was approved by the institu-
tional review board of the hospital (IRB No: KSVGH21-
CT4-03). DFO tests were performed for clinical reasons
to determine the level of aluminum toxicity in patients.
All patients who started dialysis in January 2014 and
were still on treatment on June 1, 2020, were identified
through hospital medical records. The Kaohsiung
Veterans General Hospital has routinely provided a
high-flux dialyzer for outpatient dialysis patients since
2002. All hemodialysis patients underwent three-weekly
high-flux dialysis, using a high-flux dialyzer membrane
such as Polysulfone (Asahi Kasei Medical Co., Ltd.,
Japan) and Toraysulfone (Toray Industries, Inc., Japan)
in the dialysis center. These patients underwent DFO
tests for 48 h. Briefly, 5 mg kg
-1
DFO was administered
intravenously at the end of dialysis. Aluminum concen-
trations were measured pre-DFO and 48 h post-dose
(pre-dialysis). During and after the DFO test, the hemo-
dialysis staff was asked to report any adverse events.
Patients with a clinical suspicion of aluminum toxicity
or elevated serum levels of intact parathyroid hormone
(iPTH) (>800 pg mL
-1
), indicating the need for PTX, were
included. Aluminum toxicity included symptoms of gen-
eral bone pain or proximal muscle weakness, easy frac-
ture, progressive cognitive dysfunction, unexplained
hypercalcemia, and anemia without iron deficiency under
RENAL FAILURE 1597
high-dose erythropoietin. According to the K/DOQI guide-
lines, a DFO test should be performed if there are sus-
pected clinical signs and symptoms of aluminum toxicity
or before parathyroid surgery if the patient has been
exposed to aluminum [2]. A positive DFO test (an increase
of 50 lgL
-1
in serum aluminum concentrations post-
DFO [5 mg/kg] administration)) was used to diagnose alu-
minum overload [2].
DFO treatment
The goal of treatment was to alleviate the symptoms of
aluminum overload. End-stage renal disease with alumi-
num overload was administered at a standard dose
(5 mg.kg
-1
). Two weeks before the study, patients
avoided aluminum-containing medications as much as
possible. DFO was administered once a week at a dose
(5 mg kg week
-1
) according to the K/DOQI guidelines.
Biochemical and hematological parameters and adverse
events due to DFO were also recorded.
Laboratory methods
Aluminum-free glassware and tubes were used in the
study. They were maintained in 20% (v/v) nitric acid
overnight and subsequently washed seven times with
deionized water prior to use. All reagents were of ana-
lytical grade. Ultrapure water (>18MX_cm) used
throughout this analytical procedure was prepared
using a deionized water system (Milli-Q, Millipore).
Stock solutions (1000 mg.L
-1
) of aluminum (III), supra-
pure nitric acid, and Triton-X 100 were purchased from
Merck Taiwan-Sigma-Aldrich. The serum aluminum con-
centrations were measured in the laboratory at
Kaohsiung Medical University affiliated Hospital using
an A800 atomic absorption spectrophotometer
(PerkinElmer, Norwalk, CT, USA) after suitable dilution
with 4% nitric acid (containing 0.1% Triton) solution
[23,24]. To verify the contamination of storing or pre-
paring samples in the study, ultrapure saline solutions
were used as blank samples. The aluminum levels in
blank samples were found to be below the limit of
quantification (2.2 ng L
-1
), which means that contamin-
ation of aluminum from glass devices or tubes can be
ignored under this analytical method. Quality control
was performed strictly using standard reference materi-
als with intra-assay of coefficients of variation
(ClinChekV
RSerum Control Level with a coefficient of
variation of 4.6% and Seronorm Trace Elements Serum
Control level 2 with a coefficient of variation of 5.0%).
To ensure that patients were not exposed to aluminum-
contaminated water and dialysate during HD, we col-
lected at least two dialysate samples from the inlet and
outlet of the dialysate port of the dialyzer every year to
confirm that they met the criteria of the Association for
the Advancement of Medical Instrumentation water
treatment equipment. Ten ml of blood was collected
from the vascular access of patients under-
going dialysis.
Statistical analysis
Continuous variables were checked for normal distribu-
tions using the Kolmogorov–Smirnov Ztest and
Table 1. Baseline characteristics of dialysis patients—consisted of two groups according to serum aluminum (<20 [lgL
-1
]or
20 [lgL
-1
]).
Total group Aluminum <20 Aluminum 20
pValue(n¼99) (n¼33) (n¼66)
Sex-male 54 (55%) 19 (58%) 35 (53%) 0.669
Age (year) 54.0 ± 13.2 54.1 ± 12.5 53.6 ± 14.5 0.840
Duration of dialysis(month) 49.3 ± 31.0 49.7 ± 22.3 49.1 ± 34.7 0.926
Hemodialysis/peritoneal dialysis 92 (92.9) 32 (97.0) 60 (90.9) 0.267
Hematocrit (%) 30.3 ± 5.6 30.7 ± 4.6 30.1 ± 6.0 0.655
Calcium (mg dL
-1
) 9.5 ± 1.1 9.6 ± 1.0 9.4 ± 1.1 0.573
Phosphate (mg dL
-1
) 5.7 ± 1.7 5.6 ± 1.9 5.7 ± 1.6 0.774
Alkaline phosphatase (U L
-1
) 95.2 ± 72.0 91.0 ± 49.4 97.3 ± 80.8 0.695
Intact parathyroid hormone (pg mL
-1
)669.4 ± 643.4 857.4 ± 678.8 578.3 ± 610.1 0.043
Serum aluminum (lgL
-1
) 33.1 ± 25.3 11.7 ± 5.3 43.7 ± 24.6 <0.001
Serum aluminum after DFO (lgL
-1
) 86.0 ± 53.9 35.1 ± 21.2 111.5 ± 46.8 <0.001
DAluminum (lgL
-1
) 53.0 ± 3.5 23.5 ± 16.9 67.7 ± 29.8 <0.001
Percentage of DFO positive 47 1/33 46/66 <0.001
Underlying disease (%)
CGN 28 10 18
CIN 26 11 15
DM 19 4 15
IgA nephropathy 3 0 3
Nephrosclerosis 8 1 7
Lupus 3 0 3
Others 12 5 7
DFO: desferroxime; CGN: chronic glomerulonephritis; CIN: chronic interstitial nephritis; DM: diabetes mellitus.
<0.05; <0.01.
1598 M. Y. CHEN ET AL.
compared using Student’st-test or paired t-test, if
appropriate. All continuous variables are expressed as
the mean ± standard deviation. Ordinal demographic
data were analyzed using the v
2
test or Fisher’s exact
test. The strength of correlation was obtained with the
Pearson’s correlation coefficient. Major statistical analy-
ses were performed using Statistical Package for the
Social Sciences version 15.0 (SPSS Inc., Chicago, IL,
USA). Statistical significance was set at p<0.05.
Results
Altogether, 99 patients were enrolled in the analysis, of
which 47 patients were DFO-positive (47.5%). Fifty-four
patients (iPTH:1088.9 ± 573.3 pg mL
1
) surveyed DFO
tests because of severe hyperparathyroidism (history of
iPTH >800 pg mL
1
) and were candidates for PTX. The
remaining 45 patients (iPTH:154.6 ± 191.6 pg mL
1
) had
DFO due to unexplained anemia (15 patients), relatively
low bone turnover (29 patients), and unexplained mul-
tiple rib fracture (one patient). The clinical and demo-
graphic characteristics of the participants are shown in
Tables 1 and 2, respectively.
In this study, the prevalence of the risk of aluminum
overload (serum aluminum >20 mgL
1
) was 69.7%.
There were 22 patients with serum aluminum levels
between 20 and 30 mgL
1
, 17 with serum aluminum
levels between 30 and 40 mgL
1
, and 6 patients with
serum aluminum levels between 40 and 50 mgL
1
. The
serum aluminum level was higher than 60 mgL
1
in 10
patients. The study demonstrated a positive correlation
between 䉭serum aluminum, after infusion of a stand-
ard dose of DFO and dialysis duration (r¼0.673,
p<0.001). The 10 patients with serum aluminum levels
higher than 60 mgL
1
had a trend with a relatively lon-
ger dialysis duration (65.4 ± 45.9 vs. 47.5 ± 28.7 months)
to induce aluminum accumulation (p¼0.08).
As shown in Table 1, we further used the K/DOQI
guidelines of serum aluminum 20 lgL
1
to analyze the
clinical status. However, 1 out of 33 (3.3%) patients had
aluminum levels <20 lgL
1
. Meanwhile, the 46/66
patient group had an aluminum overload of >20 lg
L
1
. Between the two groups, there were significant dif-
ferences between the serum aluminum levels, increase
in aluminum levels, positive rates of the DFO test
(p<0.001), and relatively lower intact parathyroid hor-
mone levels (p¼0.043). Patients with serum aluminum
levels >20 lgL
1
vs. those with serum aluminum levels
<20 lgL
1
showed no significant differences in age,
sex, and history of diabetes mellitus.
The baseline characteristics of the dialysis patients,
consisting of two groups according to DFO positivity or
negativity, are summarized in Table 2. There were sig-
nificant differences in serum aluminum levels, alumi-
num levels after the DFO test, and the increment in
aluminum levels after the DFO test (p<0.001). As
shown in Tables 1 and 2, serum aluminum levels were
strongly and significantly associated with an increased
risk of aluminum overload (p<0.01). Therefore, serum
aluminum level could be a predictor of aluminum over-
load. An increase in serum aluminum level by10 mg. L
1
was associated with an approximately 200% increase in
Table 2. Baseline characteristics of dialysis patients—consisted of two groups according to
deferoxamine (DFO) positive or negative.
DFO negative DFO positive
pValue(n¼52) (n¼47)
Sex-male/female 29/23 25/22 0.797
Age (year) 54.0 ± 13.2 54.1 ± 12.5 0.451
Duration of dialysis(month) 44.7 ± 22.0 54.4 ± 38.2 0.122
Hemodialysis/peritoneal dialysis 47 /5 45 /2 0.299
Hematocrit (%) 30.1 ± 5.3 30.5 ± 5.9 0.747
Mean corpuscular volume, fL 90.6 ± 8.9 89.3 ± 6.2 0.413
Calcium (mg dL
-1
) 9.6 ± 1.1 9.4 ± 1.1 0.314
Phosphate (mg dL
-1
) 5.5 ± 1.6 5.9 ± 1.8 0.186
Alkaline phosphatase (U L
-1
) 89.5 ± 50.5 101.3 ± 89.2 0.425
Intact parathyroid hormone (pg mL
-1
) 772.4 ± 708.6 557.7 ± 550.2 0.099
Serum aluminum (lgL
-1
) 18.6 ± 11.8 49.0 ± 26.7 <0.001
Serum aluminum after DFO (lgL
-1
) 46.9 ± 25.2 129.4 ± 42.8 <0.001
DAluminum (lgL
-1
) 28.3 ± 16.0 80.3 ± 25.5 <0.001
Underlying disease (%)
CGN 17 11
CIN 14 12
DM 7 12
IgA nephropathy 1 2
Nephrosclerosis 5 3
Lupus 2 1
Others 6 6
Data are expressed as mean ± standard deviation.
CGN: chronic glomerulonephritis; CIN: chronic interstitial nephritis; DM: diabetes mellitus.
<0.05; <0.01.
RENAL FAILURE 1599
the odds of aluminum overload (Table 3). Using serum
aluminum predicted aluminum overload (area under
curve: 0.904) with a cutoff level of 24 lg. L
-1
, the sensi-
tivity and specificity were 87.2 % and 76.9%, respect-
ively in this study (Figure 1)(p<0.01).
Aluminum toxicity includes the following signs and
symptoms: acute dementia, osteomalacia with bone
pain, multiple non-healing fractures, unexplained
anemia [12], and hypercalcemia occurring in these
patients when attempts are made to treat hyperpara-
thyroidism by administering calcium and 1,25(OH)
2
D
[14]. None of the patients with aluminum overload
showed overt symptoms of dementia. There were 14
(14/47) patients with symptoms that included bone
symptoms in one patient with an unexplained fracture,
unexplained anemia in eight patients requiring high-
dose erythropoietin (excluding hyperparathyroidism)
and hematological symptoms, and unexplained hyper-
calcemia in five patients (serum calcium 11 mg dL
-1
)
with relatively low bone turnover syndrome. The
remaining 33 (33/47) patients had no overt symptoms.
The mean corpuscular volume (MCV) of aluminum over-
load was approximately 89.3 ± 6.2 fL Only 4 of the 47
patients had microcytic anemia.
Four patients refused DFO treatment. Only 43
patients underwent the DFO treatment. After treatment
without parathyroidectomy, the rib fractures and hyper-
calcemia improved. Furthermore, there was a decrease
in the frequency of blood transfusion and cessation of
blood transfusion in the three patients. Eighteen
patients required at least 10 months of aluminum over-
load treatment. Twenty-five patients required less than
10 months of DFO treatment. As shown in Table 4, lon-
ger DFO treatments were especially effective in patients
with a higher increase in serum aluminum after DFO
(p¼0.041), but similar basal serum aluminum levels
(p¼0.219). After DFO treatment, there was a signifi-
cantly larger MCV (p¼0.001), decreased incidence of
microcytic anemia (p¼0.007), and a trend of increased
hematocrit (p¼0.076) (Table 5). As shown in Table 6,
DFO treatment decreased erythropoietin dosage, espe-
cially in patients with lower serum total alkaline phos-
phatase levels (<60 mL
-1
)(p¼0.028).
The K/DOQI guidelines recommend DFO for the
treatment of patients on dialysis with aluminum over-
load. However, DFO has side effects such as itchy skin,
nausea, myalgia, shock, and mucormycosis [25]. In this
study, no severe overt side effects were reported at
5mg kg
-1
per week DFO test or treatment.
Discussion
The DFO test is a noninvasive method for identifying
patients with aluminum overload. Aluminum overload
was observed in 3.3% of dialysis patients with alumi-
num <20 lgL
1
; even 69.7% of patients with levels
above the threshold had an aluminum overload. The
prevalence of patients who were DFO positive and
compatible with aluminum overload in our study was
up to 47.5%. None of the patients had neurological
symptoms, but 14 (14/47) had symptoms of aluminum
overload in the hematological and bone systems.
Furthermore, a longer treatment course of aluminum
overload was associated with a higher increase in
serum aluminum levels in the DFO test (p¼0.041), with
similar baseline serum aluminum levels.
The Kaohsiung Veterans General Hospital uses
reverse osmosis as a medical facility using water. After
reverse osmosis, water enters the dialysis water system
and encounters another reverse osmosis system and
deionization instruments. In other words, the dialysis
Table 3. Relative odds of aluminum overload by quartiles of
random aluminum levels.
Variable OR (95% Confidence interval) pValue
Baseline aluminum
(AL) <20 lgL
-1
Ref –
20 Baseline AL <30 29.09 (3.33 253.96) 0.002
30 Baseline AL <40 58.67 (6.34 542.91) <0.001
40 Baseline AL <50 160.00 (8.56 2989.45) 0.001
50 Baseline AL 320.00 (27.31 3762.85) <0.001
Figure 1. Receiver operating characteristic curve (ROC) ana-
lysis for discrimination of aluminum overload group and alu-
minum without overload group.
The ROC curve is a necessary tool for better interpretation of the results
of serum aluminum classification studies. Notably, the ROC curves are
empirical curves for sensitivity and specificity spaces.
1600 M. Y. CHEN ET AL.
water undergoes reverse osmosis twice. Using reverse
osmosis and deionization instruments, the water is con-
sidered dialysate-qualified. The water meets the criteria
of the AAMI water treatment equipment for hemodialy-
sis dialysate. The improvements in hemodialysis tech-
nology and the use of aluminum-based phosphate
binders have resulted in a low prevalence of 2% alumi-
num toxicity among hemodialysis patients in the
United States, Japan, and other countries [4–8]. Our
findings identified 47 patients (47.5%) as DFO test posi-
tive for aluminum overload. These results contradict
previous findings of a low prevalence of 2% aluminum
toxicity in the United States, but are consistent with
8%, 16.2%, and 25% of aluminum overload where the
use of aluminum-based phosphate binders is permitted
(Taiwan, Iran, Brazil) [20–22]. Indeed, there are several
other possible sources, such as bakery products and
aluminum containers. However, the prevalence of using
aluminum phosphate binders in different countries is
consistent with the difference according to the Dialysis
Outcomes and Practice Patterns Survey, which accounts
for only 0.1% of aluminum phosphate binders in the
United States dialysis centers [7]. Furthermore, the dif-
ferent results between relatively contemporaneous
groups of patients may reflect referral patterns, such as
unexplained anemia, bone fracture, and inappropriate
bone turnover due to parathyroid hormone. Based on
our findings, we believe that this problem may occur in
many countries that have not limited the use of alumi-
num-based phosphate binders because of a lack of
awareness [26].
Can single serum aluminum levels provide an indir-
ect estimation of bone aluminum content? We found
that patients with higher aluminum levels were more
Table 4. Serum basal aluminum levels and the difference in serum aluminum levels by the standard deferoxamine (DFO) test at
the standard dose (5 mg/kg) are necessary for 10 months.
<10 months of DFO
successful treatment,
medical treatment
(n¼25)
10 months of
medical treatment
(n¼18) pValue
Serum basal aluminum level (lgL
-1
) 50.4 ± 30.4 49.5 ± 23.5 0.913
Serum aluminum level (lgL
-1
) after DFO 125.2 ± 43.1 141.91 ± 43.5 0.219
Daluminum(lgL
-1
) after DFO 74.8 ± 19.1 92.4 ± 30.8 0.041
<0.05; <0.01.
Table 5. Biochemistry data using the standard deferoxamine (DFO) test at the standard dose (5 mg.kg
-1
)
for 6 months.
Parameter
Before DFO treatment
(n¼43)
After DFO treatment
(n¼43) pValue
Serum calcium (mg.dL
-1
) 9.4 ± 0.2 9.3 ± 0.2 0.404
Serum phosphorus (mg.dL
-1
) 6.1 ± 0.3 5.8 ± 0.2 0.225
Alkaline phosphatase (U.L
-1
) 97.9 ± 11.6 102.9 ± 10.9 0.413
intact parathyroid hormone (pg.mL
-1
) 503.7 ± 66.7 572.7 ± 76.4 0.281
Hematocrit (%) 31.3 ± 0.8 32.4 ± 0.8 0.076
Mean corpuscular volume, fL 89.0 ± 1.0 91.0 ± 1.1 0.001
Mean corpuscular volume<80, fL 4/39 2/41 0.007
Serum Aluminum (lg.L
-1
) 48.0 ± 23.2 37.9 ± 17.6 0.004
䉭serum aluminum (lg.L
-1
) after DFO 82.5 ± 30.8 55.4 ± 34.5 <0.001
<0.05; <0.01.
Table 6. Comparison of differences in biochemical and hematological parameters in the standard dose (5 mg kg
-1
) DFO treatment
group for 6 months.
Characteristics
Alp60(n¼13)
Before After pValue
Alp>60(n¼30)
Before After pValue
Aluminum (lg.L
-1
) 32.7 ± 3.7 35.4 ± 14.0 0.594 58.2 ± 44.0 39.0 ± 19.2 0.061
䉭aluminum(lg.L
-1
) after DFO 90.4 ± 40.0 66.1 ± 33.0 0.038 83.6 ± 27.3 51.1 ± 35.0 0.001
Calcium (mg.dL
-1
) 9.4 ± 0.8 9.4 ± 1.0 0.848 9.3 ± 1.1 9.2 ± 1.1 0.672
Phosphate (mg.dL
-1
) 6.6 ± 1.4 6.2 ± 1.4 0.506 5.8 ± 1.9 5.5± 1.7 0.222
Intact parathyroid hormone (pg.mL
-1
) 434.5 ± 447.2 431.4 ± 405.1 0.422 620.2± 604.6 751.5 ± 657.4 0.125
Hematocrit (%) 30.8 ± 4.4 31.8 ± 4.8 0.484 30.4 ± 6.6 31.2 ± 6.3 0.364
Mean corpuscular volume, fL 90.8 ± 5.4 92.8 ± 5.9 0.077 88.1 ± 6.6 89.8 ± 7.2 0.004
Erythropoietin dose changes(unit)/month 25179.5 ± 8505.6 22538.5 ± 38778.7 0.028 23691.4 ± 11607.1 22135.8 ± 11468.4 0.269
Ferritin 513.4 ± 260.7 474.1 ± 265.4 0.485 585.4± 397.0 587.5 ± 371.1 0.973
ALP: Alkaline Phosphatase.
<0.05; <0.01.
RENAL FAILURE 1601
likely to have aluminum overload than those with alu-
minum levels <20 lgL
-1
(Table 1), consistent with
reports of an association between increased serum alu-
minum levels and the incidence of aluminum overload
[2–4,27–30]. We attempted to define the value of per-
forming random tests to evaluate the levels of alumi-
num and found that this test performs very well as a
screen for aluminum overload (Tables 3 and 4and
Figure 1). Serum aluminum predicted aluminum over-
load, AUC ¼0.904, with a cutoff level of 24 lgL
1
; the
sensitivity and specificity were 87.2% and 76.9%,
respectively. In clinical practice, deferoxamine (DFO)
test should be performed if there are elevated serum
aluminum levels (60–200 mgL
1
) or clinical signs and
symptoms of aluminum toxicity [2]. However, the clin-
ical symptoms of aluminum overload are not overt. We
suggest the use of serum aluminum levels of 20 mgL
1
to screen for aluminum overload because patients with
serum aluminum levels <20 lgL
-1
had only 3.3% of alu-
minum overload. Following clinical practice with serum
aluminum levels (60–200 mgL
1
) may delay the treat-
ment of patients with aluminum overload [2].
As shown in Table 4, patients showing a higher
䉭serum aluminum after infusion of a standard dose of
DFO required a longer duration of DFO treatment
(>10 months), whereas those showing a lower 䉭serum
aluminum tended to require <10 months of treatment
(p<0.05). However, there was no difference in basal
serum aluminum levels in the two groups with a differ-
ing duration of treatment. Our study is compatible with
a previous study with similar basal aluminum levels but
different DFO test reports in patients who ingested alu-
minum hydroxide and calcium carbonate [31].
Furthermore, there was one study to point out that
baseline plasma aluminum concentrations had lower
sensitivity to predict aluminum-related osteodystrophy
(sensitivity, 43%), whereas the DFO test was found
more sensitive (sensitivity 94%) to predict aluminum-
related osteodystrophy [18]. This means that 䉭serum
aluminum, after infusion of a standard dose of DFO,
provides a more accurate estimation of the aluminum
content of the tissue and bone.
In patients with hyperparathyroidism, the parathy-
roid hormone can protect against aluminum deposition
in the bone. PTX in patients with chronic renal failure is
associated with increased aluminum deposition on the
bone surface, possibly as a result of low bone formation
[13]. The protection decreases in patients who have
undergone PTX or anti-resorption therapy or during
vitamin D treatment for hyperparathyroidism, as these
treatments could decrease bone turnover, worsen lower
turnover symptoms [32–34] and hypercalcemic
osteomalacia [14]. Considering the current case of sec-
ondary hyperparathyroidism, necessary parathyroidec-
tomy and possible anti-resorption therapy may lower
bone turnover. Therefore, it is generally suggested that
aluminum bone disease should be excluded before
lowering bone turnover treatment, such as PTX and
bone resorption therapy. Hence, early screening and
diagnosis of aluminum overload are important before
lowering bone turnover treatments.
What were the clinical symptoms of aluminum over-
load in this study? Aluminum toxicity includes the fol-
lowing signs and symptoms: (1) acute dementia, (2)
osteomalacia with bone pain, multiple non-healing frac-
tures, particularly the ribs, (3) hypercalcemia encoun-
tered in patients when medications are administered to
treat hyperparathyroidism by calcium and 1,25(OH)
2
D,
and (4) unexplained anemia. None of the patients with
aluminum overload showed overt symptoms of demen-
tia. Most of the patients were asymptomatic. Only 14
(14/47) had aluminum overload symptoms in the hema-
tological and bone systems. The symptoms improved
after aluminum chelation treatment. DFO treatment
improved the mean corpuscular volume of red blood
cells (p¼0.001) (Table 5). Previous reports have shown
that aluminum overload is associated with microcytic
anemia [12,35,36]. However, only four (4/47) of the
patients with aluminum overload showed microcytic
anemia. Most patients (43/47) with aluminum overload
did not show microcytic anemia, which is consistent
with other studies that showed no microcytosis in
patients with modest degrees of aluminum overload
[37,38]. Furthermore, DFO treatment could decrease
erythropoietin doses for anemia treatment, especially in
patients with lower bone turnover, such as those with
serum total alkaline phosphatase levels (<60 U L
1
)
(Table 6). The side effects of DFO are dose-dependent,
and common side effects have been noted with doses
of 20 40 mg kg
-1
of body weight [39–41]. The DFO
dose used in this study was 5 mg kg
-1
per week, and
there were no overt side effects during treatment. We
believe that most of these side effects are mild and are
neglected by patients and staff.
This study has some limitations. First, we used a
5mg kg
-1
dose of DFO to test for aluminum overload.
Bone biopsy is considered the gold standard method
for diagnosing aluminum overload in patients under-
going dialysis. Second, this study enrolled patients
undergoing dialysis. The number of study participants
was relatively small, even when serum aluminum and
biochemistry were checked in the same laboratory.
Additional prospective longitudinal investigations with
larger numbers of patients are necessary.
1602 M. Y. CHEN ET AL.
We conclude that although aluminum overload
exists, it might be easily ignored in the reverse osmosis
dialysis era. Aluminum overload was not associated
with any neurological symptoms in this study. In light
of the non-obvious symptoms of aluminum overload,
such as normocytic anemia and bone turnover change,
serum aluminum in dialysis patients should be moni-
tored in countries with substantial usage of aluminum-
based phosphate binders, despite the era of reverse
osmosis dialysis. Clinicians must be aware of random
aluminum levels as a test for aluminum overload and
should consider the DFO test if necessary.
Acknowledgements
The authors thank the staff at the dialysis center of
Kaohsiung Veterans General Hospital and the laboratory staff
of Kaohsiung Medical University Laboratory for their assist-
ance with data collection. The authors also express their
appreciation to the workers at the Department of Medical
Education and Research and Research Center of Medical
Informatics of Kaohsiung Veterans General Hospital for their
assistance in data processing.
Disclosure statement
No potential conflict of interest was reported by
the author(s).
Funding
The study was supported by a grant [No. KSVGH110-138 and
109-D04-1] from the Kaohsiung Veterans General Hospital,
Taiwan. The funder had no role in the study design, data col-
lection and analysis, decision to publish the manuscript, or
preparation of the manuscript.
ORCID
Nai-Ching Chen http://orcid.org/0000-0003-2684-0377
Chien-Liang Chen http://orcid.org/0000-0002-9508-8396
Data availability statement
The data generated during the current study are available
from the corresponding author upon reasonable request.
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