Alison J Roche
Iain C Macdougall
BSc MD FRCP
King’s College Hospital
Anaemia is defined as a reduction in the number of red blood cells (RBCs) in the bloodstream. It results from red cell loss (overt bleeding/trauma) or destruction (haemolysis) or from impaired red cell production. The anaemia of chronic kidney disease (renal anaemia) is defined as a chronic anaemia in which the circulating plasma erythropoietin (EPO) levels are inappropriately low for the degree of anaemia.(1) Renal anaemia usually occurs when the glomerular filtration rate falls below 30â€‰ml/min, although mild degrees of anaemia may be present up to a GFR of 60â€‰ml/min.(2) Patients with diabetes may develop renal anaemia earlier in the course of their renal ï¿½disease (ie, with a higher GFR).(3)
Patients with the anaemia of chronic kidney disease (CKD) should be screened for other causes of anaemia, including blood loss, iron deficiency, B12 and folate deficiency, malignancy, hyperparathyroidism, malignancy and infectious or inflammatory conditions. Once these conditions have been excluded, the patient may then be considered for iron supplementation, erythropoiesis-stimulating agent (ESA) therapy, or both.
Correcting iron deficiency is considered to be the first priority in treating the anaemia of CKD, and ï¿½current guidelines advocate maintaining the serum ferritin level above 200â€‰Î¼g/l (or hypochromic red cells <6%) with iron supplementation.(4) Iron supplementation may be administered orally, intramuscularly or intravenously.
Unfortunately, in patients with CKD oral iron is poorly absorbed, and it also frequently causes gastrointestinal side-effects. Intramuscular iron also cannot be recommended in CKD since the injections are painful and can result in brownish discoloration of the skin, and absorption may be unreliable. In practice, therefore, intravenous (IV) iron has been widely used in CKD, and this may be given with or without ESA therapy. It has been suggested that up to 30% of patients with early CKD may show a significant increase in haemoglobin with IV iron alone, potentially delaying the need for ESA initiation, with obvious cost benefits.(5,6) IV iron is also used in the majority of dialysis patients receiving ESA therapy where the iron losses are greater than in the predialysis CKD population. Indeed, concomitant IV iron therapy is mandatory in haemodialysis patients in order to optimise the response to ESA therapy, and studies have shown that the use of IV iron may reduce the dose requirements of ESA in this patient population.
Three IV iron preparations are available in Europe (iron dextran, iron sucrose and iron gluconate), and while all have been shown to be effective, there may be differences in the safety profile of these various agents. Anaphylactic reactions have been described with iron dextran, and while the risk of this complication is very low, the consequences can be devastating. This risk is not shared with the non-dextran-containing iron preparations (iron sucrose and iron gluconate), but “free iron” reactions characterised by dizziness and hypotension may occur if the iron is administered too rapidly. IV iron may be administered either as an infusion or a bolus injection, with the latter mode of administration potentially resulting in significant time and cost savings.(7) Other concerns with all intravenous iron preparations are increased susceptibility to infections and enhanced oxidative stress, and as a result IV iron should not be administered to CKD patients during episodes of acute infection.
In 1989, Amgen in the USA launched the first recombinant human EPO, called epoetin alfa. Amgen then retained the US licence for epoetin alfa but sold the European rights to Janssen-Cilag (now Ortho Biotech), which markets the product under the brand name Eprex(R) in Europe (Erypo(R) in Germany). The German company Boehringer Mannheim then licensed epoetin beta, which is marketed under the brand name NeoRecormon(R). Both of these epoetins have the same amino acid sequence as natural EPO, differing only in glycosylation. Another epoetin (epoetin delta; Dynepo(R)), licensed to Shire Pharmaceuticals, is about to be launched in Europe. The major difference with this product is that its manufacturing process utilises gene activation technology, and it is synthesised in a human cell line (as opposed to an animal cell line, Chinese hamster ovary cell, for the manufacture of epoetins alfa and beta).
Although all epoetins are effective in anaemia correction, they require once- to thrice-weekly administration by either subcutaneous or IV injection. This led to the development of longer-acting EPO analogues with the same biological ï¿½properties as natural or recombinant EPO, but with less ï¿½frequent dosing.
In 2001, Amgen launched the first of these longer-acting EPO analogues, called novel erythropoiesis- stimulating protein (NESP), subsequently called ï¿½darbepoetin alfa, which is marketed as Aranesp(R). It has a different amino acid sequence from the natural hormone, allowing additional carbohydrate chains to be attached. This change prolongs the terminal half-life of the EPO molecule to about three times, which allows injections to be given less frequently, either once weekly or once fortnightly.
Biosimilars: generic r-EPO
The patent for epoetin has expired in Europe and, as with any other drug, this has allowed other pharmaceutical companies to develop “generic” versions of recombinant EPO (r-EPO).
However, the advent of antibody-mediated pure red cell aplasia has highlighted the importance of the formulation of r-EPO. This has led to stringent regulations regarding the production of “generic” versions of r-EPO, and also the use of the term “biosimilar”, since it is known that these new agents will be alternative EPOs rather than identical to those currently available. The safety profile of these generic versions may not be apparent immediately, as the previous experience with epoetin alfa (Eprex(R)) has shown.
Continuous EPO receptor activator (Mircera(R))
This is likely to be the next erythropoietic agent available for the management of patients with renal anaemia. It has recently completed phase III of its clinical development programme and has been filed with the FDA and MHRA for consideration of a product licence. It was developed by the integration of a single 30â€‰kDa polymer chain into the EPO molecule, thereby increasing the molecular weight to twice that of epoetin. This larger molecule has a longer half-life (approximately 130 hours), and this allows up to once-monthly dosing.
These peptides are structurally unrelated to the EPO molecule but have the ability to mimic the functional and biological activity of EPO. The first of these compounds to reach clinical trials is called Hematide(R), which is in phase II/III of its clinical development programme. Potential advantages over existing ESAs include stability at room temperature and no cross-sensitivity with anti-EPO antibodies. This latter property may prove to be very useful in managing patients with antibody-mediated pure red cell aplasia.
Hypoxia-inducible factor (HIF) stabilisers
These products are currently in phase II of clinical development. HIF is a transcription factor that is ï¿½naturally available in the body, and which activates EPO during hypoxic conditions. HIF stabilisers inhibit the enzyme that prevents the susceptibility of HIF to degrade, thereby increasing EPO production. The key advantage of this compound is that it is orally active, and it may also have the ability to stimulate iron absorption and suppress the negative effects of proinflammatory cytokines on red blood cell production.
Correction of anaemia using iron supplementation and ESA therapy has transformed the lives of millions of CKD patients worldwide, resulting in beneficial effects on the heart(8) and on the patients’ quality of life.(9)
Since anaemia products are so lucrative, pharmaceutical companies have focused much attention on developing agents that will sustain erythropoiesis. There are currently several new agents in clinical development, as described above. Nevertheless, some hurdles with anaemia remain, such as the management of poor response to treatment, issues of nonadherence and the ability to maintain a continuous supply of drug.
- Caro J, Brown S, Miller O, et al. Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med 1979;93:449-58.
- Astor BC, Muntner P, Levin A, et al. Association of kidney function with anaemia: the third national health and nutrition examination survey (1988-1994).Arch Intern Med 2002;162:1401-8.
- Thomas MC. The high prevalence of anemia in diabetes is linked to functional erythropoietin deficiency. Semin Nephrol 2006;26:275-82.
- NICE. Anaemia management in chronic kidney disease. Clinical guideline 039. London: Royal College of Physicians; 2006.
- Roche AJ, Macdougall IC. A significant proportion of pre-end stage CKD patients show an increase in haemoglobin with IV iron alone. Nephrology 2005;10 Suppl:M-PO20079:A36.
- Mircescu G, Garneata L, Capusa C, Ursea N. Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients. Nephrol Dial Transplant 2006;21:120-4.
- Macdougall IC, Roche A. Administration of intravenous iron sucrose as a 2-minute push to CKD patients: a prospective evaluation of 2,297 injections. Am J Kidney Dis 2005;46:283-9.
- Zalunardo N, Levin A. Anemia and the heart in chronic kidney disease. Semin Nephrol 2006;26:290-5.
- Drueke TB, Locatelli F, Clyne N, et al, on behalf of the CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med 2006;355:2071-84.