The rising worldwide incidence and prevalence of chronic kidney disease (CKD) have a major impact on patient health. Up to 90% of CKD patients develop anaemia (haemoglobin levels <13.5 g/dl in men and <11.5 g/dl in women), with repercussions including reduced quality of life (QoL) and increased morbidity and mortality.(1–3) Unchecked anaemia can cause left ventricular hypertrophy, which in turn leads to cardiovascular disease, the main cause of death among CKD patients.(4) Unfortunately, anaemia is both an underrecognised and undertreated problem in CKD.(5)
Hazards of blood transfusion
Blood transfusion, pioneered by William Blundell in 1818, was the mainstay of renal anaemia therapy until the closing decades of the 20th century. Anaemic CKD patients were managed primarily by transfusions every two to three weeks. However, blood transfusions are associated with at least four types of hazard in addition to those linked to human error.(6) The first of these is infection with one of the numerous organisms transmissible via blood (such as those leading to hepatitis or HIV infection). The considerable antigenic load of blood itself may provoke hypersensitivity reactions, including potentially life-threatening anaphylaxis. Moreover, repeated antigenic challenge can sensitise the immune system, possibly compromising a kidney transplant. Finally, transfusion carries the risk of iron overload, in which surplus iron is not actively excreted and causes organ damage. Unfortunately, the total risk is cumulative for most of these hazards.
Erythropoietin (EPO), synthesised in the kidney, is central to red blood cell synthesis (erythropoiesis), so that anaemia is an inevitable consequence of renal failure.(7) In 1983, Amgen researchers led by Dr Fu-Kuen Lin used recombinant DNA technology to express the human EPO gene in cultured cells, leading to development of the first recombinant human EPO (rHuEPO, epoetin alfa; Epogen®, Amgen).(8) The overwhelming success of epoetin alfa in clinical trials led to its early market approval in the USA in 1989 and in Europe in 1990. Further EPO-based products have subsequently become commercially available (epoetin alfa: Eprex®/Erypo®, Johnson & Johnson; Procrit®, Ortho Biotech; epoetin beta: NeoRecormon®, Roche).
The first-generation erythropoiesis-stimulating agents (ESAs) have relatively short biological half-lives – 8.5 hours intravenous (IV) and 24 hours subcutaneous (SC) – necessitating administration once-weekly (QW) to thrice-weekly (TIW).(9) The disadvantages of these more frequent administration schedules are the impact on patient and physician convenience, and cost implications.(10) These factors have driven progress in this field in two directions: first, extended dosing interval studies have indicated that epoetin alfa can be administered once every two weeks (Q2W) using higher doses (10,000 IU/week); and second, new longer-life ESAs have been developed.(11)
Extended dosing with darbepoetin alfa
The half-life and biological activity of rHuEPO directly correlate with the carbohydrate content of the molecule.(12) The addition of extra sialic acid residues to rHuEPO resulted in a novel molecular entity, darbepoetin alfa (Aranesp®, Amgen), licensed in Europe and the USA in 2001. Its longer serum half-life (49 hours post-SC) allows for extended dosing intervals (Q2W), facilitating effective anaemia management in CKD patients.(13 ) A more recent study demonstrated that Q2W IV administration of darbepoetin alfa in haemodialysis patients effectively and safely maintained haemoglobin (Hb) concentrations at this less frequent dosing regimen, with no difference in dose requirements.(14) Furthermore, CKD patients treated with rHuEPO can easily be switched to Q2W or once-monthly dosing with darbepoetin alfa.(15,16)
Clinical management of anaemia with ESAs
In optimising anaemia management with ESAs, several considerations should be taken into account. For example, ESAs are currently injected either SC or IV, and require dose titration for correcting then maintaining Hb levels.(2) For CKD patients, the SC route is recommended as the most practical for pre-dialysis patients.(2,17) However, due to concerns over pure red cell aplasia (PRCA; see below), epoetin alfa is only licensed in Europe for IV use. Both epoetins alfa and beta require more drug for IV dosing than SC.(18) In contrast, doses of darbepoetin alfa are the same for both administration routes.(18)
The integration of ESAs with additional iron therapy has further improved anaemia management.(19) Recent updates of published guidelines for renal anaemia treatment endorse iron supplementation, because by improving response to ESAs, target Hb levels are reached, so reducing the need for blood transfusions and improving QoL.(2,17,20) This has been shown for epoetins alfa (QW) and beta (TIW) and for darbepoetin alfa (Q2W).(11,15,21)
Safety issues with ESAs
Overall, epoetin alfa, epoetin beta and darbepoetin alfa are generally well tolerated in CKD patients; most common side-effects include hypertension, hypotension, myalgia, diarrhoea and nausea.(22) In recent years, however, a pronounced increase in the incidence of PRCA associated with ESA treatment has attracted attention (see Figure 1). The production of neutralising antibodies inhibiting both endogenous EPO and ESAs (antibody-mediated PRCA) is rare, but has been associated with more than 200 cases where patients received epoetin alpha (mainly Eprex/Erypo) and a further eight cases with epoetin beta (NeoRecormon).(23–25) To date, only two published cases of PRCA have been observed with darbepoetin alfa.(26)
The increase in PRCA has been attributed to many factors, including route of administration, leachates from rubber bottle stoppers and changes in formulation, but causes remain unclear.
Currently, there is no evidence for an increasing trend in PRCA for Eprex/Erypo or other epoetin formulations.
Very recently, data from the CREATE and CHOIR trials, and a subsequent meta-analysis of nine ESA trials, have indicated that high Hb target concentrations (≥12 g/dl) in CKD patients may increase mortality.(27–30) However, there are limitations with these trials, including their open-label design, the underpowered nature of the CREATE trial and the high withdrawal rate in CHOIR.
Moreover, the meta-analysis dataset was dominated by data from a US trial, in which inclusion criteria included congestive heart failure or ischaemic heart disease, so patients were already at high cardiac risk.(31) Consequently, further large, randomised, controlled trials are necessary to define the optimal target Hb level in these patients.(32–34) Meanwhile, nephrologists should ensure that ESAs are used to maintain Hb levels (10–12 g/dl) as per published guidelines and the manufacturer’s prescribing information.(2,17)
The advent of ESAs as therapeutic agents for treating renal anaemia in the 1980s has transformed the management of this condition, which often used to rely on repeated blood transfusions. ESAs produce a progressive and sustained increase in Hb concentrations in CKD patients, leading to reduced hospitalisations and improved survival and quality of life.
Editorial support for this article was provided by Gardiner-Caldwell Communications Ltd, funded by an unrestricted grant from Amgen (Europe) GmbH
1. Am J Kid Dis 1999;34:125-34.
2. Nephrol Dial Transplant 2004;19(Suppl 2);ii:1-47.
3. Eur Ren Genitourin Dis 2006;1:35-8.
4. Am J Kidney Dis 1996;27:347-54.
5. Nephrol Dial Transplant 2002;17:44-6.
6. Hematol Oncol Clin North Am 2007;21:147-61.
7. Kidney Int 1997;51:622-30.
8. Proc Natl Acad Sci USA 1985;82:7580-4.
9. Nephrol Dial Transplant 2005;20(Suppl 8);viii:13-7.
10. Dial Transplant 2005;34:358-62.
11. Clin Nephrol 2005;64:113-23.
12. Br J Cancer 2001;84:3-10.
13. T Am J Nephrol 2004;24:453-60.
14. Nephrol Dial Transplant 2006;21:2846-50.
15. Am J Nephrol 2006;26:149-56.
16. Clin Nephrol 2005;63:327-34.
17. Am J Kidney Dis 2006;47(Suppl 3):S1-146.
18. Kidney Int 2002;62:2167-75.
19. Pediatr Nephrol 2007;22:480-9.
20. Cochrane Database System Review 2001;4:CD003266.
21. Clin Nephrol 1995;44:201-8.
22. Semin Nephrol 2000;20:375-81.
23. Nephrol Dial Transplant 2005;20(Suppl 4);iv:3-8.
24. Nephrol Dial Transplant 2005;20(Suppl 4);iv:9-15.
25. Port J Nephrol Hypert 2007;21:57-60.
26. Nephrol Dial Transplant 2007;22:1462-64.
27. N Engl J Med 2006;355:2071-84.
28. N Engl J Med 2006;355:2085-98.
29. Lancet 2007;369:381-8.
30. Lancet 2007;369:346-50.
31. Nephrol Dial Transplant 1998;13:3030-3.
32. Clin Nephrol 2007;In press.
33. European Renal Dis 2007; In press.
34. Port J Nephrol Hypert 2007;21:181-3.