Description of the condition
Anaemia is a common complication among patients with end-stage kidney disease (ESKD) (Eschbach 1985). Anaemia is caused by deficiency of erythropoietin (EPO), a glycoprotein produced by functioning nephrons. EPO acts on bone marrow to help mature precursor cells to mature as red blood cells. Human erythropoietin was purified, and its amino acid sequence described in the 1970s (Goldwasser 1976; Miyake 1977). Completion of a successful phase III clinical trial in 1989 prompted the US Food and Drug Administration to approve EPO for use in the treatment of anaemia of chronic kidney disease (CKD) (Eschbach 1989). EPO has since become the mainstay of anaemia management for people undergoing dialysis.
It has been estimated that at any given time 90% of prevalent dialysis patients need erythropoiesis-stimulating agent (ESA) therapy (Robinson 2012). Accordingly, several other ESAs have been introduced to the market: Epoetins (EPO-α, β, ϒ, ω) have the same amino acid sequence as endogenous EPO, but differ in the degree of glycosylation. Darbepoetin-α (epoetin analogue) is an exception, and differs from endogenous EPO at five amino acid positions and contains two additional glycosylation sites. Currently, 95% of dialysis patients in the United States are treated with EPO; and only about 4% are treated with darbepoetin (Robinson 2012).
Epoetin-α and β have comparable pharmacokinetics (Stockenhuber 1991). The terminal half-life of darbepoetin is estimated to be three times longer than intravenous epoetin-α. When studied in peritoneal dialysis patients, the time to peak concentration of darbepoetin was found to be more than double epoetin-α (54 vs. 16 to 24 hours) (Macdougall 2000) (Table 1). The newer continuous erythropoiesis receptor activator (CERA) is a post-translationally modified hyper-pegylated erythropoietin-β. The half-life of CERA is prolonged up to six days (Macdougall 2005) and can be administered once or twice a month (Sulowicz 2007).
|Intravenous route (hour)||4 to 11||8.8 to 10.4||18 to 25.3|
|Subcutaneous route (hour)||19 to 25.3||24||48||144|
|Clearance (intravenous route) (mL/hour/kg)||8.1 to 8.6||7.9||2.0|
|Bioavailability (subcutaneous route) (%)||30 to 36||15 to 50||37|
The United States Renal Data System (USRDS) has estimated the cost of ESA therapy at approximately USD 1.9 billion. With rising healthcare costs, and growing trends of bundling dialysis payment structures in Japan and the United States (Wish 2011), there is growing interest in limiting ESA usage.
Description of the intervention
ESAs (epoetins and darbepoetin) are approved for use by both subcutaneous and intravenous routes. In general, ESA administered intravenously has a shorter pharmacokinetic half-life (Table 1). Intravenous EPO requires more frequent dosing (generally three times a week) compared with subcutaneous administration (Besarab 1992). It may therefore be possible to reduce total ESA usage by using reliance on subcutaneous administration (Besarab 1992).
Widespread concern arose in the early 2000s following early reports from Europe that described pure red cell aplasia (PRCA) as a complication from subcutaneous use of EPO (Casadevall 2002). This lead to a shift from subcutaneous to intravenous route administration across dialysis facilities in North America, Europe, Japan, and Australia. Some potential advantages of subcutaneous use include lower dose requirements, and theoretically, a decreased risk of access thrombosis by avoiding exposure to high EPO concentrations and exacerbation of hypertension due to decreased peaks in EPO concentrations.
Concerns about PRCA has prompted reinvestigation of policies concerning subcutaneous EPO use. Results have indicated that red cell aplasia reporting frequency has reduced in North America (Bennett 2004). Several investigators have successfully demonstrated reductions in EPO dose requirements by switching from intravenous to subcutaneous use.
The risks of injection site pain and PRCA need to be weighed carefully against benefits obtained from subcutaneous EPO use.
Why it is important to do this review
Well designed studies (Kaufman 1998; Muirhead 1992) have shown a reduction in EPO requirements and costs of treatment by using subcutaneous EPO. Others (Jensen 1996) have failed to show a benefit of subcutaneous EPO over intravenous use. Furthermore, there is a lack of consistent estimates of reduction in dosage requirements, and resulting cost savings that may be gained from switching from intravenous to subcutaneous EPO use. As dialysis facilities throughout the world grapple with decisions to switch from intravenous to subcutaneous administration of EPO, results from this review will help to provide guidance in decision making. Our review will also aim to collate and summarise the side effect profile of intravenous versus subcutaneous EPO treatment.