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NDT Advance Access published online on November 21, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn631
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Role of medication in the level of aluminium in the blood of chronic renal patients

Denise Bohrer1, Denise C. Bertagnolli1, Sandra M. R. de Oliveira1, Paulo C. do Nascimento1, Leandro M. de Carvalho1, Solange C. Garcia2, Luiz C. Arantes3 and Elvino J. G. Barros4

1 Department of Chemistry 2 Department of Toxicology, Federal University of Santa Maria 3 Hospital of the Federal University of Santa Maria, Santa Maria 4 Clinical Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

Correspondence and offprint requests to: Denise Bohrer, Department of Chemistry, Federal University of Santa Maria, 97110-905 Santa Maria, RS, Brazil. Tel/Fax: +55-55-3220-8870; E-mail: ndenise{at}quimica.ufsm.br



   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results and discussion
 Conclusion
 Supplementary data
 References
 
Background. Although dialysis facilities provide high-quality water, abnormal aluminium levels among patients on haemodialysis have still been reported. Since patients with chronic kidney disease are often on multiple medications, medicines may be an extra source of aluminium for them. The degree to which ingesting contaminated medication influenced the level of aluminium in the patients’ blood was investigated.

Methods. All medications consumed by a group of patients on regular dialysis treatment were analysed and the total aluminium ingested by each patient was calculated. At the same time, the patients’ blood was collected and aluminium was measured. The analyses were carried out by atomic absorption spectrometry.

Results. For all drugs consumed, the amount of aluminium ingested versus the blood aluminium level presented no correlation. Since a high level of contamination was presented by injectable iron, insulin and erythropoietin (EPO), another group of patients that received a reduced amount of oral medication was selected. Among them, eight did not receive any injectable drug, five received only EPO and seven injectable iron, EPO and insulin. With these restricted groups, it was possible to show that the injectable administration of contaminated medication increased the Al level in the patients’ blood, mainly in relation to iron formulations.

Conclusion. Among the medications investigated, the injectables are the most significant source of aluminium for patients with renal insufficiency. This extra aluminium intake is reflected in higher aluminium levels in the patients’ blood.

Keywords: aluminium; elevated serum aluminium; erythropoietin; insulin; iron



   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results and discussion
 Conclusion
 Supplementary data
 References
 
Patients with chronic kidney disease on regular haemodialysis treatment are theoretically exposed to Al mainly through the water used to prepare the dialysate. This assumption is due to the enormous volume of water to which the patients are usually exposed, ~360 l/week [1]. However, with the advent of the reverse osmosis for water purification, water contamination is no longer a problem. Since the previously used aluminium-based phosphate binder [2–4] has been replaced by calcium-based binders or Sevelamer, a polymeric amine that binds phosphate, no other significant Al sources for the patients are considered.

Nevertheless, patients on regular haemodialysis treatment present abnormal plasma/serum Al levels [5]. In the United Kingdom [6], plasma Al was audited over the period of January 2000–January 2004, resulting in a collection of results for 1626 patients. The range was 1.9–817 µg/l, with a mean value of 12.7 µg/l. In the United States, a survey retrospectively examined 1410 measurements of serum Al from January 2000 to April 2003 [7]. Although Al serum values were satisfactory considering the evolution of the treatment conditions, they could not be considered within the normal range for all patients.

In an earlier work [8], we showed that the regular medication administered to the patients is contaminated by Al. Formulations containing iron and calcium presented the highest Al levels followed by calcitriol and vitamins of B complex. Moreover, injectables present much greater contamination than oral formulations, and considering the way of administration, their role in increasing the Al level in patient's blood may be significant.

Iron, besides being one of the most contaminated formulations, might indirectly enhance Al absorption. Fe may be administered along with the so-called supplementary agents, ascorbic acid, succinic acid and citrate, being the latter also used to prevent nausea caused by iron. These agents used to improve the absorption of iron stores may also promote or enhance Al absorption, since the same complexing effect these species have on Fe is displayed with regard to Al. It has been shown that citrate is a major factor in the toxicity of orally administrated Al [9–13].

We can also notice that Al and Fe play a not fully explained role in nephrogenic systemic fibrosis [14]. This is a disabling disease that occurs in patients with kidney failure exposed to gadolinium-containing contrast agents used for magnetic resonance angiography. The study has shown that Al, Fe and gadolinium are accumulated in the heart, blood vessels and skin of patients who have been exposed to gadolinium-based contrast material. The authors believe that some of the excess Al in the tissue, along with Fe, participates in the transmetallation of the gadolinium contrast. Al accumulation can only occur if it is delivered into the patient's body; therefore, it is important to know its sources.

We believe that our study, using the primary laboratory record of Al intoxication, i.e. the serum level, may help to evaluate the role of the medication in Al intake. The influence of the medication on the level of Al was investigated in the blood (serum) of patients with end-stage renal disease on regular dialysis treatment. In the first stage of the investigation, a group of patients was selected and the medications that each patient was consuming were analysed for Al quantification; at the same time, Al was also measured in the blood of these patients. In the second stage, another group of patients, who were taking a reduced quantity of oral medications, was selected. This group included both those patients who consumed injectables and who did not consume injectables, namely, iron supplements, EPO and insulin. Again, the medications and the patients’ blood were analysed for Al quantification.



   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results and discussion
 Conclusion
 Supplementary data
 References
 
Patients and blood samples
Twenty patients on regular haemodialysis treatment at the Casa de Saúde Hospital (Santa Maria, Brazil) and 20 patients on CAPD at the University Hospital (at the Federal University of Santa Maria) were selected for the study. The blood was collected during the haemodialysis session following a protocol previously established [15]. Blood samples were centrifuged for serum separation. Before the measurement, samples were deproteinized by the combined action of trichloroacetic acid and microwave irradiation [15]. All steps of sample preparation were conducted under laminar flow (class 100). Aluminium was measured by graphite furnace atomic absorption spectrometry (GF AAS) under the conditions described in Table 1 in the supplementary data available online.

The dialysis concentrate used to prepare the dialysate was the same (from the same lot) for all patients, as well as the dialysis solution used by patients on CAPD. Since the medication taken by the patients, with the exception of calcium carbonate, was furnished by the hospital, it was simple to collect samples from the same lot that was given to the patients for each medicine.

Apparatus
A Varian SpectrAA-200 atomic absorption spectrometer equipped with a GTA-100 graphite furnace and an auto sampler (Varian, Melbourne, Australia), a Trox class 100 clean bench (Trox, Curitiba, Brazil), a domestic microwave oven (Philips, São Paulo, Brazil), a Jouan C412 centrifuge (Jouan, St Herblain, France) and a Berghof BSB 939-IR sub-boiling distillation apparatus (Berghof, Eningen, Germany) were used.

Reagents
The water used throughout was distilled, deionized and further purified by a Milli-Q high-purity water device (Millipore, Bedford, MA, USA). An aluminium standard solution containing 1000 mg/l Al (Merck, Germany) was used to prepare the working standard solutions. HNO3 [65% (m/m), 1.17 g/ml] from Merck was further purified by sub-boiling distillation.

Contamination control
To avoid contamination, only plastic materials were used. All laboratory ware (pipette tips, volumetric flasks, etc.) were immersed for at least 48 h in a 10% (v/v) HNO3/ethanol solution and, shortly before use, washed with Milli-Q purified water. To avoid contamination from the air, all steps in the sample and reagent preparation were carried out in a class 100 clean bench.

Analysis of medications
Because the Al level in these samples can vary from microgram to milligram per gram, the measurement was carried out by atomic absorption spectrometry either using flame (FAAS) or graphite furnace (GF AAS) according to the Al concentration. All samples were processed according to a procedure described elsewhere [8]. For all products, at least three samples of the same lot were analysed, and the results reported correspond to the mean value.

Calculation of aluminium ingestion
Based on the results of the medication analysis, it was possible to calculate the Al amount in each dose of medicine. The Al ingested by each patient, was calculated by multiplying the amount of Al present in the medicine by the dose given to the patient. Since the frequency of administration varies from drug to drug and from patient to patient, the calculation was done on a weekly basis.



   Results and discussion
Top
 Abstract
 Introduction
 Material and methods
 Results and discussion
Conclusion
 Supplementary data
 References
 
The first step was to calculate the Al ingested by each patient through medication. The most consumed medicines were analysed. Knowing the Al level in the products consumed by the patients and the dose administered to each one, the calculation was carried out on a weekly basis, in order to include all the medications taken by the patient. Table 1 presents this calculation, carried out for 20 patients, including the Al present in each dosage and the total amount ingested. Besides the total amount, Table 1 also presents the amount of Al taken orally and intravenously.


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  		Table 1 Aluminium ingested together with the medication by different patients in 1 week

 
The graphics presented in Figure 1 correlate the serum Al level to the amount of Al taken with the medication. When the total amount was considered, no correlation was observed (Figure 1a); however, when only injectable Al was considered, it was observed that an increase in the Al ingested corresponded to an increase in the Al serum level (Figure 1b). This result may be explained by the fact that when Al ingested orally is to be considered, Al present in food and water should also be computed, which is a calculation not easy to do [16]. Moreover, because orally ingested Al is mostly eliminated through the intestinal tract, the fraction reabsorbed into the circulatory system is difficult to calculate.


Figure 1
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  		Fig. 1 Serum Al of patients on dialysis treatment as a function of the Al ingested via medication in 1 week. (a) Total Al ingested; (b) Al administrated intravenously.

 
In order to have better control of the variables, another group of patients that received a reduced amount of oral medication was selected. Only the Al received intravenously by the patients was computed. Among these patients, eight received no intravenous medication, five only EPO, one only insulin, one iron and insulin and five iron and EPO. A new lot of each medication (those that were being administered to the patients during the time of the blood collection) was evaluated for its Al level. These values, presented in Table 2, are not very different from those obtained in the first part of the study. Table 2 shows the amount of Al ingested by each patient together with the selected medication per week. The relationship between Al ingested and Al in serum can be observed in Figure 2. Patients not receiving intravenous medications presented Al serum levels <10 µg/l, and for those taking only EPO or insulin, the Al level was not significantly higher. On the other hand, for patients taking EPO, insulin and iron, the Al serum level was significantly higher, 22.1 ± 9.0 µg/l versus 6.7 ± 2.4 µg/l (mean of the first group). The differences between the groups were evaluated by one-way ANOVA (P < 0.05). It is clear that, among the patients that received injectables, the higher Al levels were presented by the patients receiving iron, which is not only the most contaminated formulation, but also the one administered in greater amounts.


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  		Table 2 Aluminium administrated together with the injectable medication to different patients in 1 week

 

Figure 2
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  		Fig. 2 Serum Al of patients on dialysis treatment as a function of the Al ingested via medication in 1 week. aStatistically different (P < 0.05) by one-way ANOVA.

 


   Conclusion
Top
 Abstract
 Introduction
 Material and methods
 Results and discussion
 Conclusion
Supplementary data
 References
 
Since the patients were treated in the same clinics, the dialysates were a collective and identical Al source for all patients, and could therefore be excluded from the sum of the Al ingested.

Including a great number of patients on different medications hindered a clear evaluation of the influence of this source of Al in the patients’ blood. Moreover, other sources such as drinking water and foodstuff may play a role when the intake of Al through medication is not so high.

The Al level found in patients receiving the injectable drugs, iron, insulin and EPO, three of the most important and widely administered medications for dialysis patients, is high in comparison to the patients who do not receive these products. This shows that these formulations may be a significant contribution to higher Al levels in blood.

Aluminium exposure in chronic renal disease is a well-recognized problem and is credited to the water and dialysate for patients on regular dialysis treatment. Medications, however, are also a source of Al, mainly those given intravenously, which, similar to dialysate, face no barriers to enter the patients’ circulatory system.



   Supplementary data
Top
 Abstract
 Introduction
 Material and methods
 Results and discussion
 Conclusion
 Supplementary data
References
 
Supplementary data are available online at http://ndt.oxfordjournals.org.



   Acknowledgments
 
We are thankful to the nursery staff of both hospitals for their assistance in collecting the samples.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Material and methods
 Results and discussion
 Conclusion
 Supplementary data
 References
 

  1. Daugirdas JT, Blake PG, Ing TS. Handbook of Dialysis (2007) 4th edn. Boston, MA: Little, Brown and Co.
  2. Persy VP, Behets GJ, Bervoets AR, et al. Lanthanum: a safe phosphate binder. Semin Dial (2006) 19:195–199.[CrossRef][Web of Science][Medline]
  3. Storms LE, Chicella MF, Dice JE. Sevelamer therapy for pediatric end-stage renal disease. Pharmacotherapy (2006) 6:410–413.[CrossRef]
  4. Coladonato JA. Control of hyperphosphatemia among patients with ESRD. J Am Soc Nephrol (2005) 16(Suppl_2):S107–S114.[Abstract/Free Full Text]
  5. Kausz AT, Antonsen JE, Hercz G, et al. Screening plasma aluminum levels in relation to aluminum bone disease among asymptomatic dialysis patients. Am J Kidney Dis (1999) 34:688–693.[Web of Science][Medline]
  6. Gault PM, Allen KR, Newton KE. Plasma aluminium: still necessary for patients on renal dialysis? Ann Clin Biochem (2006) 43:51–54.
  7. Jaffe JA, Liftman C, Glickman JD. Frequency of elevated serum aluminium levels in adult dialysis patients. Am J Kidney Dis (2005) 46:316–319.[CrossRef][Web of Science][Medline]
  8. Bohrer D, Bertagnolli DC, Oliveira SMR, et al. Drugs as a hidden source of aluminium for chronic renal patients. Nephrol Dial Transplant (2007) 22:605–611.[Free Full Text]
  9. Kirschbaum BB, Schoolwerth AC. Acute aluminum toxicity associated with oral citrate and aluminum-containing antacids. Am J Med Sci (1989) 297:9–11.[Web of Science][Medline]
  10. Gomez M, Domingo JL, Llobet JM. Developmental toxicity evaluation of oral aluminum in rats: influence of citrate. Neurotoxicol Teratol (1991) 13:323–328.[CrossRef][Web of Science][Medline]
  11. Coburn JW, Mischel MG, Goodman WG, et al. Calcium citrate markedly enhances aluminum absorption from aluminum hydroxide. Am J Kidney Dis (1991) 17:708–711.[Web of Science][Medline]
  12. Taylor GA, Moore PB, Ferrier IN, et al. Gastrointestinal absorption of aluminium and citrate in man. J Inorg Biochem (1998) 69:165–169.[CrossRef][Web of Science][Medline]
  13. Sherrard DJ. Aluminum—much ado about something. New Engl J Med (1991) 324:558.[Web of Science][Medline]
  14. Swaminathan S, High WA, Ranville J, et al. Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis. Kidney Int (2008) 73:1413–1418.[CrossRef][Web of Science][Medline]
  15. Bohrer D, Nascimento PC, Pomblum SG. Deproteinization of blood serum by acid treatment and microwave irradiation for the determination of aluminium by electrothermal atomicabsorption spectrometry. J Anal At Spectrom (1998) 13:635–639.[CrossRef]
  16. Oliveira SMR, Bertagnolli DC, Bohrer D, et al. Serum aluminium: influence of water and food consumed by patients with chronic renal insufficiency on regular hemodialysis treatment. J Bras Nefrol (2005) 27:101–109.
Received for publication: 24. 4.08
Accepted in revised form: 20.10.08


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