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NDT Advance Access originally published online on September 27, 2009
Nephrology Dialysis Transplantation 2009 24(12):3899-3900; doi:10.1093/ndt/gfp514
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© The Author 2009. Published by Oxford University Press [on behalf of the ERA-EDTA]. All rights reserved.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses?by-nc/2.0/uk/) which permits unrestricted non-commercial use distribution, and reproduction in any medium, provided the original work is properly cited.


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Nephrol Dial Transplant 2009; doi:10.1093/ndt/gfp508

E-mail: clotilde-muller{at}hotmail.fr

In response to Dr Smyth's letter to the editor, we would like to remind readers that lanthanum carbonate has indeed shown its efficacy, but that many safety concerns remain unsolved. We would like to draw attention to two main points brought out in our case report:

1.  Gastro-intestinal effects: Lanthanum has been shown to induce a number of gastrointestinal effects [1].

Patients with acute peptic ulcer, ulcerative colitis, Crohn disease or bowel obstruction were not included in the pivotal FOSRENOL(R) study, its 6-year follow-up report [2] or in Finn's work [3]. Therefore, caution should be exercised in patients with these conditions [4]. There was more withdrawal in patients treated with lanthanum mainly attributable to digestive disorders in these studies. Our patient had previous digestive disorders and therefore should be considered a high-risk patient for digestive side effects.

In our patient, the plasmatic lanthanum level was 2.13 µg/l. In the public assessment report [5], the mean concentration for long-term ingestion of 3 g lanthanum/day ranges from 0.5 to 0.6 ng/ml. There was no significant dose or time effect on treatment. Altman's study reported the same mean plasmatic value—0.3 ng/ml—but a wide range (0.0–3.1 ng/ml). More information would be required to explain this difference.

It has been shown that the tissue concentration is higher than the plasma concentration so we cannot assume that lanthanum is not nontoxic. Tissue accumulation is seen particularly in the gastro-intestinal tract, lymphoreticular system, bone, liver and spleen [5]. Recently, Davis and Jerrold reported the detection of lanthanum deposits in a mesenteric lymph node in a patient 3 years after exposure [6].

The degree of digestive absorption has not been evaluated, nor has the excretion of the unabsorbed dose of lanthanum in the faeces been demonstrated in humans [5,7].

The two FDA reviewers for market approval of lanthanum (Drs Pelayo and Oluferni [1]) made a negative recommendation because of the gastro-intestinal effects and the unknown accumulation and elimination of the product, which presented ‘a real risk of malnutrition and additional injury in this population’. They stated that it can be ‘unacceptably toxic’. The sponsor was in charge of providing proof on this point but was unable to do so.

2.  The effects on the central nervous system: a number of animal studies indicate significant brain exposure [8].

The blood–brain barrier can be damaged when there is significant inflammation, tumours, etc. and can allow selective delivery of pharmacological agents to the brain [9]. The impact of lanthanide on brain function is not insignificant [10]. It is known that when it passes the blood–brain barrier in animals, it can be toxic to the nervous system and cognition [11,12]. In healthy rats, Damment et al. [13] showed that the lanthanum brain concentration found is considered contamination.

There is insufficient evidence to conclude that lanthanum cannot cross the blood–brain barrier in healthy or uraemic patients, not to mention infected haemodialysed patients.

Many publications agree that further investigation and more time are needed before it can be firmly concluded that the tissue accumulation is nontoxic, with no severe adverse effects [14].

The Transparency Committee of the French National Authority for Health (Haute Autorité de Santé) has stated that safe long-term use of lanthanum is not established given that it accumulates in bone, brain and heart.

We fully agree with Smith and Pratt that the benefice-risk ratio need not to be revised based on our case report alone. However the nephrological community needs to be reminded that a product's safety, especially in dialysis patients, is the cornerstone of patient care. We merely emphasize that this medication should not be used in the case of inflammatory or gastro-intestinal disorders since none of the studies conducted to date have included patients with these pathologies [1–3]. In addition, the product label clearly states that the product should not be administered to these patients [5,15]. Our article is a reminder that prescription of this medication is restricted and a warning that previously reported adverse effects may occur.

Conflict of interest statement. None declared.

Muller Clotilde, Chantrel Francois and Faller Bernadette

Nephrology Department, Hopital Civil de Colmar, France

References

  1. U.S. Food and Drug Administration. (2004) 180. Application number: 21-468. Medical review 13 October.
  2. New six-year data supports FOSRENOL(R) as a treatment choice for end-stage renal disease patients, November, 12, 2004. (Paper written after the poster presented in the American Society of Nephrology 2004).
  3. Finn WF, Joy M, LAM-308 Study Group. A long term, open label extension study on the safety of treatment with lanthanum carbonate, a new phosphate binder, in patients receiving haemodialysis. Curr Med Opin Res (2005) 21:657–664.[CrossRef]
  4. Finn WF. Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance hemodialysis patients. Clin Nephrol (2006) 65:191–202.[Web of Science][Medline]
  5. Public Assessment report Scientific discussion Fosrenol July 12, 2006 SE/H/481/01-04/E01.
  6. Davis RL, Jerrold L. A lanthanum deposition in a dialysis patient. Nephrol Dial Transplant (2009) 24:3247–3250.[Abstract/Free Full Text]
  7. Damment SJ, Pennick M. Clinical pharmakocinetics of the phosphate binder lanthanum carbonate. Clin Pharmacokinet (2008) 47:553–563.[CrossRef][Web of Science][Medline]
  8. Lacour B, Lucas A, Auchere D, et al. Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration. Kidney Int (2005) 67:1062–1069.[CrossRef][Web of Science][Medline]
  9. Davies DC. Blood brain barrier breakdown in septic encephalopathy and brain tumours. J Anat (2002) 200:639–646.[CrossRef][Web of Science][Medline]
  10. Fan GQ, Yuan ZK, Zheng HL, et al. Study on the effects of exposure to rare earth elements and health responses in children aged 7–10 years. J Hyg Res (2004) 33:23–28.
  11. Feng LX, Xiao HQ, He X, et al. Long term effects of lanthanum intake on the neurobehavioral development of the rat. Neurotoxicol Teratol (2006) 28:119–124.[CrossRef][Web of Science][Medline]
  12. Zhu WF, Xu SQ, Shao PP, et al. Biolelectrical activity of the central nervous system among population in a rare earth element area. Biol Trace Elem Res (1997) 57:71–77.[CrossRef][Web of Science][Medline]
  13. Damment SJP, Cox AG, Secker R. Dietary administration in rodent studies distorts the tissue deposition profile of lanthanum carbonate; brain deposition in a contamination artifact? Toxicol Lett (2009) 188:223–229.[CrossRef][Web of Science][Medline]
  14. Drüeke TB. Lanthanum carbonate as a first line phosphate binder: the ‘cons’. Semin Dial (2007) 20:329–332.[CrossRef][Web of Science][Medline]
  15. FOSRENOL. Summary of Product Characteristics (2007) Basingstoke: Shire Pharmaceutical Contracts Ltd.

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Related articles in NDT:

A confusional state associated with use of lanthanum carbonate in a dialysis patient: a case report
Michael D. L. Smyth and Raymond D. Pratt
NDT 2009 10.1093/ndt/gfp508. [Extract] [FREE Full Text]  




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