Treatment of renal anaemia
Anaemia Treatment In CKD Patients
Anaemia in the presence of CKD can increase the risk for adverse outcomes, including mortality, progression of kidney disease, CVD, stroke, hospitalisation, and diminished quality of life.1 Therefore, patients with early kidney disease should be carefully monitored and treatment with an ESA initiated as soon as anaemia is diagnosed, before Hb concentration falls to a level that is likely to induce serious and possibly irreversible sequelae. (CKD-related anaemia is defined as Hb levels consistently below 11 g/dL [haematocrit <33%] where all other causes of anaemia have been excluded.)2 The benefits of ESAs include increased Hb levels, reduced need for blood transfusion, and improved quality of life and exercise capacity.
Clinical Practice Guidelines
Clinical practice guidelines have been developed to facilitate the management of anaemia in patients with CKD (Table 1). The overall goal of the guidelines, which address such topics as the use of new erythropoietic agents, iron supplementation, adjunctive therapies, adverse events (AEs), and appropriate target Hb levels, is to help clinicians provide better medical care of their patients with CKD-related anaemia, thereby improving their physical status and quality of life.
Target Hb levels: Reflecting current European clinical practice and experience, the EBPG recommends maintaining a target Hb level of >11 g/dL, with individualisation for patients with significant comorbidities, such as severe CVD, diabetes, sickle-cell disease, and chronic hypoxaemic pulmonary disease.2 The NKF/KDOQI guidelines also recommend a similar target level (≥11.0 g/dL) for patients with CKD. Importantly, they note that there is insufficient evidence to recommend routinely maintaining Hb levels >13.0 g/dL in ESA-treated patients.
Higher Hb values are associated with lower relative risk of hospitalisation and mortality in patients with CKD.3 In DOPPS, the relative risk of hospitalisation was reduced by 6% for every 1 g/dL increase in Hb. Compared with the reference Hb level of 11-11.99 g/dL, the relative risk of hospitalisation was significantly increased at Hb concentrations below 10 g/dL - 1.55 at Hb <8 g/dL (P<0.0001) and 1.16 at Hb 8-9.99 g/dL (P=0.001) - but was not significantly reduced at concentrations of ≥12 g/dL (1.01, P=0.77).3
An analysis of three European surveys of anaemia management in patients with CKD found that most patients do not start to receive treatment with ESAs until they reach stage 5 CKD and are undergoing dialysis.4 These agents are used relatively infrequently in patients with stages 1 through 4 CKD and anaemia who are not on dialysis, even when Hb concentrations are below the level at which initiation of epoetin is recommended by the EBPG.4
The EBPG recommend maintaining a target Hb level of >11 g/dL, with individualisation for patients with significant comorbidities, such as severe CVD, diabetes, sickle-cell disease, and chronic hypoxaemic pulmonary disease.
Erythropoiesis-Stimulating Agents
Five ESAs are currently approved for treatment of anaemia in CKD patients:
- Epoetin alfa Eprex®/Epogen®/Procrit®/Erypo®)
- Epoetin beta (NeoRecormon®/Recormon®/Epogin [in Japan])
- Darbepoetin alfa (Aranesp®/Nespo®)
- Epoetin delta (Dynepo™)
- MIRCERA (methoxy polyethylene glycol-epoetin beta), the first and only continuous erythropoietin receptor activator.
| Name (year) | Country (patient group) | Treatment initiation | Target Hb levels |
|---|---|---|---|
| Anaemia Management in People with Chronic Kidney Disease (2006)61 |
England and Wales (National Institute of Health and Clinical Excellence [NICE]) (patients with CKD) |
Hb ≤11 g/dL | Hb 10.5–12.5 g/dL |
| Caring for Australasians with Renal Impairment (CARI) (2005)62 |
Australia (dialysis patients) |
Not specified but recommended minimum Hb 11.0 g/dL |
Hb 12.0–14.0 g/dL (≤12 g/dL in patients with proven or likely CVD) |
| EBPG (2004)7 | Europe (patients with CKD) |
Hb <11.0 g/dL Haematocrit <33% |
Hb >11.0 g/dL Haematocrit >33% (Hb >12.0 g/dL not recommended in severe CVD; Hb >14.0 g/dL not desirable in haemodialysis patients) |
| Clinical practice guidelines for the management of anemia coexistent with chronic renal failure (1999)63 |
Canada (Canadian Society of Nephrology) (patients with CKD) |
Variable among patients, usually ~10.0 g/dL |
Hb 11.0–12.0 g/dL |
| NKF/KDOQI Guidelines (2006)50 |
United States (NKF) (patients with CKD) |
Hb <11.0 g/dL | Hb ≥11 g/dL (caution when intentionally maintaining Hb >13 g/dL) |
The pharmakokinetic properties of the shorter-acting ESAs (epoetin alfa, epoetin beta, darbepoetin alfa and epoetin delta) are compared in Table 2.
| IV | SC | ||||
|---|---|---|---|---|---|
| Half life | Volume of distribution | Half life | Tmax | Bioavailability | |
| Eprex (epoetin alfa)64 |
4–5 h | ~24 h | 12–18 h | 20% | |
| NeoRecormon( epoetin beta)65 |
4–12 h | 1–2 x plasma volume | 13–28 h | 12–28 h | 23–42% |
| Aranesp (darbepoetin alfa)66 |
21 h | ~plasma volume (50 mL/kg) |
73 h with monthly administration 0.6–2.1 µg/kg |
37% | |
| Dynepo (epoetin delta)67 |
5–13 h (~50% shorter in healthy subjects) |
~total blood volume; range, 63–97 mL/kg |
27–33 h | 8–36 h | 26–36% |
Tmax = time to maximum serum concentration
ESAs target the erythropoietin receptor to stimulate RBC production by erythroid precursors in the bone marrow. Endogenous erythropoietin consists of a central polypeptide core with posttranslationally linked carbohydrates. Epoetin alfa, epoetin beta and darbepoetin alfa are produced in Chinese hamster ovary cell lines; epoetin delta is produced in a human cancer cell line through gene activation.5 Darbepoetin alfa has a higher degree of glycosylation (5 N-linked carbohydrate chains versus 3 in the epoetins and endogenous erythropoietin), which is accommodated by five changes in the amino acid sequence of the peptide backbone compared with endogenous erythropoietin.6,7 The hyperglycosylated structure results in a longer serum half-life and higher relative potency than epoetin, allowing the administration interval of darbepoetin alfa to be extended in selected patients beyond that possible for epoetin.8
Existing agents all have different recommended dosing schedules (adult patients):
- For epoetin alfa, dosing is three times weekly (TIW) intravenous (IV) and subcutaneous (SC).
- For epoetin beta, dosing is once weekly (QW) SC to TIW IV and SC. In addition, for patients stable on a QW SC epoetin beta regimen, the interval may be extended to once every 2 weeks (Q2W) SC.
- For darbepoetin alfa, dosing is QW IV and SC or Q2W IV and SC. Only those patients not on dialysis and stable on Q2W SC dosing may have their dosing interval extended to Q4W SC.
- For epoetin delta, dosing is TIW IV or twice weekly SC.
| Patient group | Route | Dose | |
|---|---|---|---|
| Eprex (epoetin alfa)64 |
Haemodialysis Peritoneal dialysis Chronic renal failure not on dialysis |
IV IV or SC IV or SC |
50 IU/kg, TIW 50 IU/kg, twice weekly 50 IU/kg, TIW |
| NeoRecormon (epoetin beta)65 |
Chronic renal failure
|
IV SC |
40 IU/kg, TIW 20 IU/kg, TIW |
| Aranesp (darbepoetin alfa)66 |
Chronic renal failure Chronic renal failure not |
IV or SC SC |
0.45 µg/kg (QW) 0.45 µg/kg (QW) or |
| Dynepo (epoetin delta)67 |
Chronic renal failure |
IV SC |
50 IU/kg TIW 50 IU/kg twice weekly |
Starting doses for the shorter-acting ESAs are shown in Table 3
The use of ESAs has advanced the management of CKD-related anaemia, but shorter-acting treatments have significant limitations.9 These include Hb cycling (fluctuations in Hb over time, which may result in damage to tissues of target organs); frequent dosing, which is burdensome for patients, nurses, and administrators; and the limited availability of extended dosing. (Only a small percentage of patients in real practice qualify, so most patients do not have an opportunity to go to extended dosing.) There is also a concern that the current pharmacological approach to treatment of anaemia in CKD, particularly with shorter-acting drugs when extended administration intervals are used, may induce neocytolysis (destruction of young RBCs),10 by producing sharp peaks in serum erythropoietin levels, followed by rapidly falling levels.11
References:
1. McClellan WM, Jurkovitz C, Abramson J. The epidemiology and control of anaemia among pre-ESRD patients with chronic kidney disease. Eur J Clin Invest. 2005;35(Suppl 3):58-65.
2. Locatelli F, Aljama P, Bárány P, Canaud B, Carrera F, Eckardt KU, Hörl WH, Macdougall IC, Macleod A, Wie,cek A, Cameron S; European Best Practice Guidelines Working Group. European best practice guidelines for the management of anaemia in patients with chronic renal failure, Revised 2004. Nephrol Dial Transplant. 2004;19(Suppl 2):ii1-ii47.
3. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:94-111.
4. Valderrábano F. Anaemia management in chronic kidney disease patients: an overview of current clinical practice. Nephrol Dial Transplant. 2002;17(Suppl 1):13-18.
5. Dynepo™ Summary of Product Characteristics. Shire Pharmaceuticals Ltd. July 2006. http:/anti-infectives/Paris-Event/Live-Webcast.cfmwww.emea.europa.eu/humandocs/PDFs/EPAR/dynepo/H-372-PI-en.pdf
6. Macdougall IC, Gray SJ, Elston O, Breen C, Jenkins B, Browne J, Egrie J. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392-2395.
7. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer. 2001;84(Suppl 1):3-10.
8. Deicher R, Hörl WH. Differentiating factors between erythropoiesis-stimulating agents: a guide to selection for anaemia of chronic kidney disease. Drugs. 2004;64:499-509.
9. Collins AJ, Brenner RM, Ofman JJ, Chi EM, Stuccio-White N, Krishnan M, Solid C, Ofsthun NJ, Lazarus JM. Epoetin alfa use in patients with ESRD: an analysis of recent US prescribing patterns and hemoglobin outcomes. Am J Kidney Dis. 2005;46:481-488.
10. Rice L, Alfrey CP. The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem. 2005;15:245-250.
11. Fishbane S. Recombinant human erythropoietin: has treatment reached its full potential? Semin Dial. 2006;19:1-4.
