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NDT Plus 2009 2(Supplement 1):i1-i2; doi:10.1093/ndtplus/sfn173
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© The Author [2009].
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

This article appears in the following NDT Plus issue: Key Insights into Present and Future Treatments of Anaemia in CKD Patients [View the issue table of contents]

Key insights into present and future treatments of anaemia in CKD patients

Angel L. M. de Francisco

Servicio de Nefrología, Hospital Universitario Valdecilla, Santander, Spain

Correspondence: Angel L. M. de Francisco, Presidente de la Sociedad Española de Nefrología, Servicio de Nefrología, Hospital Universitario Valdecilla, Santander, Spain. Tel: +34-942-202738; Fax: +34-942-320415; E-mail: martinal{at}unican.es

Key Words: anaemia management • chronic kidney disease • erythropoiesis-stimulating agents • haemoglobin levels

Received for publication September 19, 2008. Accepted for publication October 21, 2008.


   Introduction
Top
 Introduction
References
 
The introduction of erythropoiesis-stimulating agents (ESAs) revolutionized the management of anaemia in chronic kidney disease (CKD) patients by providing effective control of haemoglobin (Hb) levels, reducing the need for blood transfusions and improving patient quality of life. The use of ESAs in CKD patients is constantly evolving as new research helps us to better understand how to safely and effectively manage anaemia in these patients. This supplement reviews the latest thinking on optimal Hb control and looks to the future in the increasingly complex landscape of ESA therapies.

Anaemia has been recognized as a risk factor for the development of cardiovascular disease (CVD) in CKD patients and CVD remains the leading cause of hospitalization and death in these patients. In their chapter entitled ‘Future perspectives on treatment with erythropoiesis stimulating agents’ in high-risk patients, Stefan Anker and Robert Toto review several large-scale clinical studies designed to address the question of whether effective management of anaemia can improve cardiovascular (CV) outcomes. Results of the CHOIR [1] and CREATE [2] studies are discussed, along with two more recent studies, TREAT (Trial to Reduce cardiovascular Events with Aranesp Therapy) [3,4] and the RED-HF (Reduction of Events with Darbepoetin alfa in Heart Failure) trial [5], which are currently ongoing. The latter randomized controlled studies are anticipated to shed light on ESA safety at higher target Hb levels and it is hoped that they will provide the conclusive data still needed to establish the impact of anaemia therapy on CVD in these patients.

In their chapter entitled ‘Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations’, Fernando Carrera and Michel Burnier provide an overview of the use of the ESA, darbepoetin alfa (Aranesp®), in the treatment of anaemia in CKD patients. Darbepoetin alfa, the first longer-acting ESA, has been shown to offer a number of further clinical and economic benefits over the shorter-acting epoetins, epoetin alfa and beta. Several studies are discussed, which demonstrate that patients either not on dialysis or receiving dialysis can be successfully switched from epoetin to darbepoetin alfa at extended dosing intervals, with no compromise in efficacy and with significant dose savings. In addition to the convenience afforded by extended dosing intervals, pharmacoeconomic implications are also considered. The MERCURIUS study is expected to provide further information on how improvements could be made in all stages of ESA delivery and utilization in hospitals throughout Europe. Interim data from one centre demonstrate significant cost savings in labour and materials following a switch from epoetin to darbepoetin alfa therapy.

Hb levels that are either too high or too low can have an adverse effect on patient outcomes. Evidence from CHOIR [1] and the Normal Haematocrit Trial [6] has shown that targeting higher versus lower Hb levels (13.5 versus 11.3 g/dL and 14 versus 10 g/dL, respectively) results in an increase in the risk of death and serious CV events in CKD patients. In light of this, and other emerging evidence, treatment targets have recently been re-assessed by regulatory agencies. In the latest revision (March 2008) of the European product labelling (SmPC) for the ESA class of drugs, the target treatment range was lowered to 10–12 g/dL, with a warning not to exceed 12 g/dL [7–13]. It is clear that optimal control of Hb levels is both desirable and essential, yet maintaining patients at Hb levels that are both safe and provide maximal benefit is a continuing challenge. Hb levels in CKD patients have been shown to move up and down during treatment, sometimes with quite extreme fluctuations above and/or below target Hb ranges; it is important, therefore, to understand the causes of Hb fluctuation or variability in order to optimize treatment. Inflammation is believed to play a key role in Hb variability and responsiveness to ESAs in CKD patients. Our third paper, entitled ‘Inflammation and its impact on anaemia in chronic kidney disease: from haemoglobin variability to hyporesponsiveness’, by Angel L. M. de Francisco, Peter Stenvinkel and Sophie Vaulont addresses the complex role of inflammation in CKD, as evidenced by the apparent state of deranged inflammatory markers.

It has been suggested that increased levels of pro-inflammatory cytokines in CKD suppress bone marrow erythropoiesis, reduce erythropoietin production and modulate iron metabolism leading to hyporesponsiveness to ESAs and poor treatment outcomes [14,15]. The mechanisms by which inflammatory cytokines may affect the response to ESAs are examined. In addition, the authors discuss a number of possible strategies or interventions with which to minimize inflammation in these patients and enhance response to ESAs.

In addition to the increasing complexity of maintaining patient Hb levels within narrower margins, the number of available treatment options is also rising, not only with respect to new ESAs, but also with the recent market entry of epoetin biosimilars. Biosimilar molecules are defined as ‘biological products referring, but not identical, to existing products, submitted for separate market approval following patent expiration.’ In the final paper of the supplement, entitled ‘Biosimilar therapeutics-what do we need to consider?’, Dr Huub Schellekens highlights some important issues surrounding biosimilars, including variability and inconsistency in structure and purity, the impact of this variability on patient safety and the need for further regulations (to supplement those currently in place) for their approval and use.

In summary, this supplement provides an informative discussion of the important issues of the day surrounding the use of ESAs in patients with CKD. Ongoing research, discussed herein, will continue to enlighten this complicated area, ultimately leading to safer more effective use of these agents.


   Acknowledgements
 
Medical writing support was provided by Jane Blackburn, PhD, Gardiner-Caldwell Communications.

Conflict of interest statement. This manuscript was sponsored by Amgen (Europe) GmbH. Angel L. M. de Francisco is a member of the Medical Advisory Board of the Fresenius-Amgen sponsored ARO Research Study group. He has given lectures at scientific meetings arranged by Amgen and by Roche. He has also received fees from Johnson & Johnson.


   References
Top
 Introduction
 References
 

  1. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med (2006) 355:2085–2098.[Abstract/Free Full Text]
  2. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of haemoglobin levels in patients with chronic kidney disease and anemia. N Engl J Med (2006) 355:2071–2084.[Abstract/Free Full Text]
  3. Mix TC, Brenner RM, Cooper ME, et al. Rationale-Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J (2005) 149:408–413.[CrossRef][Web of Science][Medline]
  4. Schmidt R, Dalton C. Treating anemia of chronic kidney disease in the primary care setting: cardiovascular outcomes and management recommendations. Osteopath Med Prim Care (2007) 1:14.[CrossRef][Medline]
  5. Young JB, Anand IS, Diaz R, et al. Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF)TM Trial [abstract 950169]. Poster presented at 10th Annual Scientific Meeting of the Heart Failure Society of America, 10–13 September 2006, Seattle, WA, USA.
  6. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared to low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med (1988) 339:584–590.[CrossRef]
  7. Eprex® SmPC, Janssen-Cilag, 2008. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=889 (11 September 2008, date last accessed).
  8. Aranesp® SmPC, Amgen, 2008. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=4981 (11 September 2008, date last accessed.
  9. NeoRecormon® SmPC, Roche, 2008. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=7747 (11 September 2008, date last accessed.
  10. MIRCERA® SmPC, Roche, 2008. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=19960 (11 September 2008, date last accessed.
  11. Abseamed® SmPC, Medice Arzneimittel Pütter, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/abseamed/H-727-PI-en.pdf (11 September 2008, date last accessed.
  12. Binocrit® SmPC, Sandoz, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/binocrit/H-725-PI-en.pdf (11 September 2008,date last accessed.
  13. Epoetin alfa HEXAL® SmPC, HEXAL Biotech Forschungs GmbH, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/epoetinalfahexal/H-726-PI-en.pdf (11 September 2008, date last accessed.
  14. Mueller HJ, Hahn K, Schneider HW, Wanner C, Mann J. Contributing factors to Hb-cycling in a large cohort of ESRD patients in Germany [abstract SA-PO019]. Presented at American Society of Nephrology Annual Congress, 14–19 November 2006, San Diego, USA.
  15. Locatelli F, Andrulli S, Memoli B, et al. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant (2006) 21:991–998.[Abstract/Free Full Text]

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