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Hematological and Neurological Side Effects Associated with the
Use of Aluminum Based Phosphate Binders in Dogs with
Chronic Kidney Disease
Segev, G.,1* Naylor, S.2 and Cowgill, L.D.3
School of Veterinary Medicine, the Hebrew University of Jerusalem, P.O. Box 12, Rehovot, 76100, Israel.
Veterinary Teaching Hospital, University of California, Davis, CA, USA.
3
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA.
1
2
* Corresponding author: Dr. Gilad Segev, School of Veterinary Medicine, PO 12, Rehovot, Israel. Email: gilad.segev@mail.huji.ac.il
The patients were treated at the William R. Pritchard Veterinary Medical Teaching Hospital, University of California, Davis, One Shields
Avenue, Davis, California 95616-8747.
AB S T RAC T
Hyperphosphatemia and secondary hyperparathyroidism are common in dogs with chronic kidney disease
(CKD). It was hypothesized that dogs with CKD managed with aluminum-based phosphate binders
accumulate aluminum, and may present clinical signs of toxicity. Fifty two client-owned dogs with CKD were
examined in this retrospective study. Dogs diagnosed with CKD that were managed with aluminum based
phosphate binders for at least 45 days and had complete blood count available were included, and followed
for up 120 days. Blood samples for aluminum concentration were drawn directly into plastic syringes using
a newly placed peripheral intravenous catheter. The mean aluminum concentration for dogs was measured
to 0.12±0.13 ppm (range, 0.031-0.52 ppm) (reference range < 0.08 ppm). Eighteen dogs were suspected of
having aluminum toxicity. The average aluminum daily dose in those dogs was significantly higher compared to
dogs for which aluminum toxicity was not suspected (117.4±63.7 vs. 71.5±40.3 mg/kg/day, P = 0.002). Clinical
signs suspected to result from aluminum toxicity were ataxia, altered mentation, paraparesis, tetraparesis, and
decreased peripheral reflexes, decreased papillary light response and tremor. The most pronounced changes
documented in dogs were progressive decrease in mean corpuscular volume and hemoglobin concentration.
Both were found as reliable predictors of aluminum accumulation as well as sensitive and specific markers. It
was concluded that dogs with CKD accumulate aluminum and are prone to aluminum toxicity. Progressive
decrease in MCV and MCH should alert clinicians to aluminum accumulation. Dogs with advanced CKD
managed with high aluminum doses should be screened routinely for aluminum accumulation.
Keywords: Hyperphosphatemia; Hyperparathyroidism; Binders; Neurological signs; Sevalamir;
Lanthanum.
INTRODUCTION
Chronic kidney disease (CKD) is common in dogs (1).
Hyperphosphatemia and secondary hyperparathyroidism are
inevitable consequences and expected features of the disease
(2). The latter has been shown to be associated with rapid
progression of the disease in human patients and in dogs
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(3, 4). Normalization of serum phosphorus concentration
is a mainstay of the management of CKD, and is usually
achieved by a combination of feeding low phosphate diets
and administration of intestinal phosphate binding agents
that further minimize intestinal absorption of phosphorus.
Intestinal phosphate binding agents can be divided to aluAluminum Toxicity in Dogs
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minum based, calcium based or non-aluminum non-calcium
based (e.g., sevalemer, lanthanum). The most commonly used
phosphate binders in veterinary medicine are aluminum or
calcium based. Both types are effective and inexpensive,
but may promote adverse effects. Calcium based phosphate
binders may cause or aggravate hypercalcemia, thus cannot
be used in hypercalcemic patients or in patients that develop hypercalcemia during the treatment. Aluminum-based
binding agents are used commonly in veterinary medicine
because they are effective, inexpensive, and are associated
with relatively few reported side effects. Nevertheless, as
aluminum is eliminated primarily by the kidneys, patients
with advanced CKD and reduced excretory capacity that
are being supplemented with aluminum based phosphate
binders may accumulate aluminum in their tissues in toxic
concentrations. In contrast to the relatively limited reports
of side effects associated with the use of aluminum based
phosphate binders in veterinary medicine (5), aluminum
toxicity is a well documented phenomenon in human CKD
patients who are managed with aluminum based phosphate
binders. It has been shown that human CKD patients who
are managed with aluminum based phosphate binders accumulate aluminum in their body tissues, including in the
brain (6).There is also an association between aluminum
accumulation and the development of Alzheimer’s disease
(7). Reported side effects in human CKD patients include
encephalopathy, microcytic anemia, and osteomalacia (8-12).
These side effects have prompted a near discontinuation of
aluminum-based phosphate binding agents in human CKD
patients (13). Due to the risk for aluminum accumulation
and toxicity, human CKD patients who are managed with
aluminum-based phosphate binding agents are screened
routinely for potential toxicity (14).
Aluminum is eliminated primarily by the kidneys; therefore, it is likely that dogs with CKD that are managed with
aluminum based phosphate binders accumulate aluminum
in their tissues, as has been documented in other species (5).
A case report of two dogs with aluminum toxicity and their
successful treatment with deferoxamine (Deferoxamine,
500mg/vial Inj., Desferal, Schaffhauserstrasse, Switzerland)
has been published (5). The lack of recognition of aluminum
toxicity in dogs is probably multi-factorial. Firstly, dogs may
be less susceptible to aluminum toxicity compared to human patients. Secondly, human patients with more advanced
CKD are being managed with high doses of aluminum based
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Segev, G.
March 2016.indb 32
phosphate binders and for longer periods compared to dogs.
Thirdly, veterinarians may not be aware of this intoxication
and thus may not recognize the symptoms associated with
the disease. Fourth, signs of aluminum toxicity may be very
subtle, as has been observed in human patients (e.g., speech
disturbances and variable degrees of dementia) (15, 16), and
consequently may go unnoticed in dogs or alternatively may
be attributed to complication of the kidney disease per se (i.e.
uremia, hypertension).
The objectives of this study were: 1) to assess whether
dogs with CKD and treated with aluminum-based phosphate
binding agents accumulate aluminum. 2) to characterize the
side effects associated with the use of aluminum based phosphate binders, and 3) to identify early markers of aluminum
accumulation that can alert clinicians to possible intoxication.
MATERIAL AND METHODS
Dogs
Dogs presented to the Medicine Service of the Veterinary
Medical Teaching Hospital (VMTH) at UC Davis,
California, and diagnosed with CKD were considered for
inclusion. Chronic kidney disease was diagnosed based on
persistent (> 4 weeks) renal azotemia, low urine specific gravity and chronic renal changes upon ultrasound examination.
Only dogs managed for at least 45 days with aluminum based
phosphate binders were included in the study. These dogs
were followed as long as aluminum was administered for up
to 120 days. Dogs for which a complete blood count (CBC)
was not available at initiation of therapy or dogs that did
not have at least two CBCs performed during the follow-up
period were excluded from the study.
Laboratory data
Complete blood counts and serum chemistries were performed at the VMTH laboratory. In order to follow trends
in complete blood count parameters for the first 120 days
following aluminum initiation the data was portioned to 30day intervals. When dogs had more than one value within
each interval, parameters were averaged. When aluminum
toxicity was suspected by the attending clinician, aluminum concentration was measured on serum samples at the
Utah Veterinary Diagnostic Laboratory (Utah Veterinary
Diagnostic Laboratory, Logan, UT, USA). Blood samples
for aluminum concentration were drawn directly into plastic
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syringes through newly placed peripheral intravenous catheter, to prevent contact of the sample at with any form of
glass or metal.
Statistical analysis
Normality of continuous variables was assessed using the
Shapiro-Wilk test. Data were described as mean±SD when
normally distributed and as median and range when not
normally distributed. Continuous variables were compared
between study groups using the student t-test when normally
distributed and by the Mann-Whitney-U test when not
normally distributed. The changes in the CBC parameters
over time and the comparison between the study groups were
performed using repeated measures ANOVA. The proportion
of different abnormalities was compared between the study
groups using the Chi square test. Correlations between the
maximal drop in mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH) and mean corpuscular
hemoglobin concentration (MCHC) and the serum aluminum concentration was assessed using the Spearman rank
correlation test. A receiver operating characteristics analysis
was performed to assess the different variables as predictors
of aluminum accumulation and to calculate the sensitivity
and specificity. The optimal cutoff point was the point associated with the least number of misclassifications. Analysis
was performed using a statistical software (SPSS 17.0 for
Windows, Chicago, IL). For all tests applied, P < 0.05 was
considered statistically significant.
RESULTS
Signalment
Fifty-two dogs fulfilled the inclusion criteria and were included in the study, of those 18 dogs were suspected of having
aluminum toxicity. The mean age of all dogs was 7.9±4.1
years. Dogs that were suspected of having aluminum toxicity were significantly younger compared to dogs in which
aluminum toxicity was not suspected (6.1±4.2 vs. 8.8±3.8
years, P = 0.02). Fourteen dogs were mixed breed and the rest
were pure breed. There were 29 female dogs (all spayed) and
23 males (16 castrated). The mean body weight of all dogs
was 21.2±13.8. There was a statistically significant difference
in body weight between dogs in which aluminum toxicity was
suspected and dogs that were not (26.4±17.7 vs. 18.4±10.6
kg, P = 0.05).
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Overall, 21 dogs were managed with hemodialysis, at least
partially, during the study period. The proportion of dogs that
were managed with hemodialysis was significantly higher
among dogs for which aluminum toxicity was suspected (61%
vs. 42%, P = 0.04).
Aluminum dose and blood concentration
The average aluminum dose for all dogs was 87.4±53.7 mg/
kg/day (range, 13.5-244.3 mg/kg/day). The average aluminum
dose in dogs for which aluminum toxicity was suspected was
significantly higher compared to those that were not suspected
of having aluminum toxicity (117.4±63.7 vs. 71.5±40.3, P =
0.002). The average treatment time with aluminum in this
study was 166±153.5 days with no statistically significant
difference in the mean treatment time between dogs that were
or were not suspected of having aluminum toxicity.
Aluminum serum concentration was measured only in
dogs when aluminum accumulation/toxicity was suspected,
based on the clinician discretion, mostly when dogs were
medicated with aluminum based phosphorous binders for a
relatively long period time, a high dose was used, or the dog
presented neuroloical signs. The aluminum concentration was
above the reference range in all dogs for which aluminum
samples were obtained. The mean aluminum concentration
of these dogs was 0.12±0.13 ppm (range, 0.031-0.52 ppm)
(reference range <0.08 ppm). Iron and total iron binding
capacity was measured in 15/18 dogs in which aluminum
toxicity was suspected with an average of 172±224 µg/dL
and 397±228 µg/dL, respectively.
Clinical signs associated with aluminum accumulation
Overall 18/52 dogs (34.6%), treated with aluminum hydroxide, were suspected of having aluminum toxicity/accumulation. Of these, nine dogs presented clinical signs that were
suspected to result from aluminum toxicity. These included
ataxia (4 dogs), altered mentation (2 dogs), paraparesis (2
dogs), tetraparesis (6 dogs), decreased peripheral reflexes (2
dogs), decreased papillary light response, and tremor (1 dog
each). The remaining dogs were suspected of having aluminum toxicity/accumulation due to high dose of aluminum
used and/or prolonged treatment time.
Clinicopathologic data
Initial serum creatinine for all dogs was 6.2±4.7 mg/dL.
Serum creatinine was significantly higher in dogs for which
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aluminum toxicity was suspected (8.9±4.7 vs. 4.8±2.9 mg/
dL, P < 0.001, reference range 0.5-1.4 mg/dL)). Phosphorus
concentration prior to the initiation of treatment initiation
was 9.1±4.7 mg/dL (reference range 2.5-5.8 mg/dL), and was
not significantly different between the two groups.
At initiation of therapy with aluminum based phosphate
binders, the mean complete blood count parameters were all
within the reference range with the exception of decreased
hematocrit (30±6.7%, reference range 37-55%). The average
of the mean corpuscular volume (MCV), mean corpuscular
hemoglobin (MCH) and the mean corpuscular hemoglobin
concentration (MCHC) were 68.0±4.4 fl (reference range,
65-75), 23.4±1.8 pg (reference range, 22-26), and 34.6±1.5
g/dL (reference range, 33-36), respectively. The most pronounced complete blood count changes observed over the
study period in all dogs were progressive decreases in MCV
and MCH. During the initial 30, 60, 90 and 120 days the
MCV decreased compared to the baseline in 1.1%, 4.5%,
7.1% and 9.1%, respectively (Figure 1). The decrease in MCV
during the study period was significantly (P <0.001) greater at
all time points in dogs for which aluminum toxicity was suspected compared to dogs for which toxicity was not suspected
and aluminum serum concentration was not obtained (2.6%,
8.5%, 12.9%, 15.7% compared to 0.06%, 2.4%, 3.3%, 5.1%)
(Figure 2). Repeated measures ANOVA revealed significant
(P < 0.001) interaction between the two groups, with dogs in
which aluminum toxicity was suspected having a more rapid
decrease in MCV over time compared to dogs in which toxicity not suspected. The maximal change observed in MCV
during the study period for all dogs was 10.5±7.8%, for dogs
with suspected aluminum toxicity 15.6±8.7% and for dogs
with no suspected toxicity 7.7±5.8%. There was a statistically significant difference in the maximal drop in MCV
between the two latter groups (P < 0.001). No significant
correlation was found between the maximal drop in MCV
and the aluminum serum concentration in dogs when it was
available. The prevalence of microcytosis (MCV<65 fl) also
increased during the study period. After 30, 60 and 90 days of
aluminum administration the proportion of microcytosis was
32%, 61% and 75%, respectively. Finally, the maximal change
in MCV was found to be a good predictor of aluminum
accumulation. An ROC analysis revealed an area under the
curve (AUC) of 84%. An MCV of 58 fl was found to be
the optimal cutoff point, corresponding to sensitivity and
specificity of 78% and 85%, respectively.
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Segev, G.
March 2016.indb 34
The trend in the MCH was a similar to that trend observed for MCV, with significant decrease in MCH over
time, significant difference between the two groups and a
significant interaction between the groups. The maximal
change in MCH for all dogs was 9.4±8.5%, for dogs with
suspected aluminum toxicity 14.3±9.1% and for dogs that
were not suspected of toxicity 6.9±7.0%. As in MCV, there
was a statistically significant difference between the two latter
groups (P < 0.001). The maximal change in MCH was also
found a good predictor of aluminum accumulation with an
AUC of 87%. The optimal cutoff point was MCH of 18pg,
corresponding to sensitivity and specificity of 83% and 97%,
respectively.
Contrary to MCV and MCH, there were no statistically
significant changes over time in MCHC and in hematocrit
during the initial 120 days from initiation of aluminum
based phosphate binders. Iron and total iron binding capacity
were not measured routinely in the entire study population,
nonetheless, it was available in 12 of the 18 dogs that were
suspected to have aluminum toxicity and was found to be
within the reference range in all.
DISCUSSION
This current study has demonstrates that aluminum, when
administered to dogs with CKD to control hyperphosphatemia and secondary hyperparathyroidism, accumulates in
dogs, and may be associated with clinical signs. Therefore,
proper monitoring and awareness are required.
Chronic kidney disease is common in dogs, and hyperphosphatemia is an expected and inevitable consequence of
the disease (4). Phosphorous restricted diets and phosphate
binding agents are the mainstay of therapy of hyperphosphatemia and secondary hyperparathyroidism (17). Aluminum
hydroxide has been used routinely in veterinary patients
as a phosphate binding agent; however toxicity was rarely
documented (5), thus is considered safe in dogs and cats. It
is plausible that the apparently low frequency of aluminum
toxicity documented in dogs compared to human patients
relates to lower doses of aluminum used in dogs, shorter
periods of administration time, less advanced kidney dysfunction, species differences, and a combination of the above. It is
also possible that the apparently lower incidence of aluminum
toxicity relates to clinicians’ awareness of this problem and
the misconception that aluminum accumulation does not
exist in dogs.
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In animals, aluminum salts are probably less likely
to achieve concentrations associated with overt clinical
manifestations due to relatively short life spans or due to
sub-therapeutic doses. Nevertheless, guidelines for control
of serum phosphorus concentration in dogs with CKD have
become more exacting, necessitating the use of high doses
of phosphate binders. In addition, as knowledge increases,
animals with advanced disease can now be managed for
longer period of times. The combination of high doses of
aluminum based phosphate binders and longer periods of
administration in dogs with limited excretory capacity increases the risk of aluminum toxicity. In the current study,
dogs in which aluminum toxicity was suspected, had a more
severe azotemia (i.e., lower excretory capacity), and were
managed with significantly higher mean aluminum hydroxide
doses, compared to those that were not suspected of having
aluminum accumulation. These findings demonstrate that the
combination of a high aluminum hydroxide dose in dogs with
severe kidney dysfunction predispose these dogs to aluminum
accumulation. Moreover, serum aluminum concentrations
were invariably above the reference range when measured,
indicating that dogs with advanced CKD that are managed
with aluminum based phosphate binders, do in fact accumulate aluminum, as has been shown in human patients. It
is likely that the true incidence of dogs that have significant
aluminum accumulation is higher than documented in this
study as only a subset of patients had their aluminum serum
concentration measured. On the other hand the high prevalence documented in this study might have been influenced
by the VMTH being a tertiary referral center. Consequently,
patients presented with more advanced kidney disease, and,
possibly, higher doses of aluminum based phosphate binders
are more readily prescribed.
In the current study, 21 dogs were managed, at least partially, during the study period with hemodialysis. It has been
Figure 1:
a: Changes in mean corpuscular volume over time of all dogs receiving
aluminum based phosphorous binders.
b: Changes in mean corpuscular volume over time of dogs receiving aluminum
based phosphorous binders and not suspected of having aluminum toxicity.
c: Changes in mean corpuscular volume over time of dogs receiving aluminum
based phosphorous binders suspected of having aluminum toxicity.
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shown that aluminum accumulation in human patients who
are managed chronically with hemodialysis may be due to
aluminum contamination of the dialysate (14). In the current
study hemodialysis probably did not play a role in aluminum
accumulation, even in patients that were managed with hemodialysis for a long period of time, as the water quality was
routinely measured and aluminum was always undetectable.
Nevertheless, in patients treated chronically with hemodialysis this possibility should always be considered. The high
prevalence of aluminum accumulation among dogs managed
with hemodialysis is probably related to the higher degree of
renal dysfunction of these patients, higher doses of aluminum
hydroxide used, increased awareness of clinicians managing
these dogs, or a combination of the above.
The clinical signs that were attributed to aluminum
accumulation were mostly neurologic and included ataxia,
altered mentation, paraparesis/tetraparesis and decreased
peripheral reflexes. It cannot be excluded that other more
subtle clinical signs, as observed in human patients with aluminum accumulation, were more prevalent among dogs with
aluminum accumulation, but went unnoticed or alternatively
were not attributed to aluminum accumulation. Therefore, it
is the authors’ opinion that aluminum accumulation should
be considered in the differential diagnoses for all dogs with
Figure 2: Maximal documented decrease in MCV from baseline
(in percentage) of all dogs receiving aluminum based phosphorus
binders. The reference MCV was the one documented just before
the initiation of aluminum based phosphorous binders.
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Segev, G.
March 2016.indb 36
CKD that are managed with aluminum-based phosphate
agents, even when only subtle neurological signs are present.
Moreover, in the presence of advanced CKD and the use
of high doses of aluminum binders, routine screening for
serum aluminum concentration should be considered, as is
recommended for human patients (18).
The most common clinicopathologic abnormalities observed in the study were progressive microcytosis and progressive decrease in MCH. The decrease in both parameters
was significantly higher among dogs in which aluminum
toxicity was suspected, implying a possible correlation between the degree of aluminum accumulation and the degree
of microcytosis. Nevertheless, there was no statistically significant correlation between the maximal drop in MCV and
the measured serum aluminum concentration. This finding
may be related to the partial correlation between the serum
aluminum concentration and the tissue concentration (19).
Progressive microcytosis is also a well documented phenomenon in human patients with aluminum toxicity and in animal models (20). The exact pathophysiology of microcytosis
associated with aluminum toxicity is undetermined, however
it is suggested that increased aluminum concentrations may
interfere with iron metabolism, since the decrease in MCV
is similar to the expected with iron deficiency, however, iron
supplementation cannot reverse or prevent the microcytosis
associated with aluminum toxicity (21). The cause of progressive microcytosis may be difficult to distinguish initially
from iron deficiency associated with erythropoietin therapy
in uremic animals (22). Nevertheless, in the current study
the routine use of iron dextran along with the erythropoietin
therapy make iron deficiency less likely to be the cause for
the progressive microcytosis. Since progressive microcytosis
is a consistent finding among species (e.g., human, rodents,
dogs) (21, 23, 24) it is likely that the presence of microcytosis
can be used as an early indicator for aluminum accumulation
in CKD patients treated with aluminum-based phosphate
binders after the exclusion iron deficiency. This is further
supported by the high area under the ROC curve and high
sensitivity and specificity of MCV as predictor of aluminum
accumulation.
The elimination of aluminum from uremic animals that
are symptomatic for aluminum toxicity remains problematic.
Aluminum discontinuation should be the first step when
toxicity is suspected or documented. Deferoxamine has been
used successfully as an aluminum-chelating agent in human
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patients, laboratory animals and in dogs (5, 25, 26). The coupling of deferoxamine chelation with hemodialysis is likely
more effective, since the kidney is the primary route for the
elimination of the chelated aluminum, and its clearance will
be significantly impaired in patients with poor renal function
(26).
There are a few limitations to this study. First, the number
of dogs for which aluminum concentration was available is
limited decreasing the power of the statistical comparisons.
Second, clinical signs that might have resulted from aluminum toxicity may not have been attributed to aluminum
accumulation, due to a lack of awareness, thus the incidence
of aluminum toxicity might have been an underestimation
of its true prevalence. Third, this is not a controlled study,
therefore some of the clinical signs and clinicopathologic
abnormalities that were attributed to aluminum accumulation
might not have been related to aluminum administration
alone, but rather were a consequence of the kidney disease per
se. Thus, the association between aluminum and clinical and
clinicopathologic signs can be pointed out, but a cause and
effect relationship cannot be proven. Nevertheless, based on
the current knowledge, most of the observed signs were less
likely to develop due to kidney disease in the absence of aluminum administration. Forth, in some cases, aluminum blood
concentration might have been obtained after a progressive
microcytosis, which was refractory to iron supplementation,
was noted; therefore, in these dogs microcytosis might have
been the trigger to suspect aluminum accumulation. If this
was the case, the prevalence of microcytosis might have been
higher in dogs in which aluminum toxicity was suspected due
to bias by selection. Fifth, aluminum concentration was not
measured in all dogs in the current study, thus it cannot be
excluded that some of the dogs for which aluminum accumulation was not suspected had high aluminum concentration
as well, and therefore were not included in the dogs with
aluminum toxicity. Finally, tissue aluminum concentration
was not measured in any of the dogs in this study thus the
correlation between tissue and blood aluminum concentration cannot be made.
In summary, aluminum accumulates in dogs with CKD
that are managed with aluminum based phosphate binders,
as has been shown in other species. All dogs in this study
that had their aluminum blood concentration measured had
abnormally high concentrations. Neurological signs were
the most common clinical manifestation of dogs with aluIsrael Journal of Veterinary Medicine  Vol. 71 (1)  March 2016
March 2016.indb 37
minum accumulation, however, these were not consistent
within the study group, thus the possibility for aluminum
accumulation should be suspected in any dog with CKD
that is managed with aluminum based phosphate binders and
presents neurological signs. The most common clinicopathologic abnormalities noted were progressive microcytosis and
a decrease in MCH, therefore the aforementioned findings
(when refractory to iron supplementation) can be used as
early indicators of aluminum accumulation.
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