Description of the condition

Anaemia has been defined by the World Health Organization (WHO) as a haemoglobin concentration less than 13.0 g/dL and 12.0 g/dL respectively for males and non‐pregnant females aged 15 years or over (WHO 2008). This definition is widely accepted for people with anaemia caused by CKD (KDIGO 2012).

Anaemia is a common complication in people with CKD and develops early in the course of the disease. Anaemia increases in frequency with a corresponding decline in kidney function, and peaks in incidence among people with ESKD (Astor 2002). Kidney‐related anaemia develops mainly as a consequence of relative EPO deficiency in relation to haemoglobin levels; EPO levels are 10 to 100 times higher among anaemic patients with normal kidney function (Artunc 2007; Ly 2004; McGonigle 1984).

Description of the intervention

EPO is an essential growth factor for the recruitment, differentiation, maintenance and survival of erythroid progenitor cells. EPO is produced by hepatocytes in the foetal stage, and after birth is synthesised mainly by the kidneys in response to hypoxia (Glaspy 2009; Jelkmann 2011). After cloning the EPO gene in 1983, recombinant human technology enabled development and production of the first erythropoietin ‐ epoetin‐α ‐ which was approved for clinical use in 1989 (Eschbach 1988; Eschbach 1989). Since then, many EPO types ‐ also called erythropoiesis‐stimulating agents (ESAs) ‐ have been produced. According to their action time, they are classified as short‐acting and long‐acting (Horl 2013).

Short‐acting ESAs have a half‐life from six to eight hours intravenously and from 19 to 24 hours subcutaneously; most are administered two to three times weekly (Halstenson 1991). Short‐acting ESAs are more effective when administered subcutaneously. Alfa and beta are the most widely used short‐acting ESAs. Epoetin‐α biosimilars are used in Europe (Schellekens 2008).

Long‐acting ESAs have improved pharmacokinetic and pharmacodynamic characteristics. Dose requirements do not differ according to the route of administration. The combination of a significantly increased half‐life and lower binding affinity for the EPO receptor explains why long‐acting ESAs stimulate erythropoiesis for longer periods. Long‐acting ESAs used for the treatment of kidney‐related anaemia are darbepoetin‐α and the continuous EPO receptor activator (CERA). One darbepoetin dose is given every one or two weeks (Macdougall 1999; Padhi 2006) and CERA is administered biweekly or monthly (Macdougall 2006).

EPO therapy improves cognitive function and quality of life (Astor 2002; Drueke 2006; Pfeffer 2009; Ross 2002) and helps regression of left ventricular hypertrophy (Levin 2002; Parfrey 2009). However, EPO is not free of complications which are mainly hypertensive reactions, thrombosis of arteriovenous fistula in patients on haemodialysis, increased risk of stroke and faster tumour growth; appearance of severe anaemia as part of pure red cell aplasia, and seizures (Del Vecchio 2010; Rizzo 2010; Zhu 2006).

How the intervention might work

EPO acts as an essential growth factor. It regulates erythropoiesis, maintaining the survival of erythroid progenitors, stimulating their proliferation and differentiation in the bone marrow (Jelkmann 2011). EPO production is markedly up‐regulated by hypoxia via a negative feedback loop; hypoxia induces an increase in EPO hormone production in the kidneys, increasing the mass of circulating red blood cells, thereby increasing the oxygen‐carrying capacity of blood and suppressing further expression of EPO (Bunn 2013). Specifically, EPO binds to the EPO receptor through the high affinity isoform EPO, which is responsible for the erythropoietic effects by activation of several pathways (hypoxia‐inducible factor 1, 2 and 3, Janus kinase‐2, phosphatidylinositol 3‐kinase, protein kinase C, anti‐apoptotic protein) stimulating differentiation of erythroid precursor cells and inhibiting apoptosis of erythroid progenitors (Elliott 2008; Sinclair 2013).

Recombinant human EPO and human EPO have similar biological activity. Increase in red blood cell mass is dependent on the exposure time of the level of EPO; therefore, subcutaneous administration of short‐acting ESAs is more effective (Kaufman 1998). The response to administration of EPO may vary from patient to patient. The dose should be adjusted to reach a haemoglobin monthly increase between 1 and 2 g/dL. If the increase is less than expected, the dose is increased by 25%; if higher, it is decreased by 25%. After reaching the target haemoglobin level, the maintenance dose of EPO is adjusted according to monthly haemoglobin readings (Del Vecchio 2010; KDOQI 2006; KDIGO 2012).

Why it is important to do this review

The importance of this systematic review is based on the following premises.

1. Many of the clinical manifestations of CKD may be epiphenomena of anaemia, which is associated with the worsening of cognitive functions, exercise capacity, mental acuity, quality of life; depression and fatigue (Finkelstein 2009; Gerson 2004; Weisbord 2008). Increased risk of cardiovascular morbidity and mortality may also be present (Astor 2006; Glassock 2009; Locatelli 2004).

2. ESAs have changed treatment of kidney‐related anaemia by improving the signs and symptoms of severe anaemia, avoiding the complications of iron overload, transmission of viral diseases and sensitisation for future kidney transplants (Del Vecchio 2010). However, no benefits have been found in RCTs and meta‐analyses when correcting anaemia with regard to patients’ mortality and non‐cardiac fatal events, except for quality of life (Drueke 2006; Johansen 2010; Johansen 2012; Pfeffer 2009). Notwithstanding, a relationship between the use of ESAs and an increased cardiovascular morbidity and mortality in patients with CKD has been reported in studies with fully correcting anaemia comparing with partial anaemia correction (Palmer 2010; Phrommintikul 2007; Singh 2006). Patients with cancer also experience increased cardiovascular morbidity and mortality associated with ESA use (Rizzo 2010; Tonia 2012).

3. From 2000 to 2009 clinical guidelines from the United States and Europe recommended commencing ESA treatment when haemoglobin was less than 11 g/dL (EBPG 2004; ERBP 2009; ERBP 2010; KDOQI 2000; KDOQI 2006; KDOQI 2007; KDIGO 2008). The 2012 Anaemia Work Group of Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggested starting treatment in dialysis patients when haemoglobin is between 9 to 10 g/dL (Grade 2B), and in some cases, starting treatment when haemoglobin is greater than 10 g/dL (not graded), primarily in older people among whom life expectancy is limited, being more relevant to improve quality of life (KDIGO 2012). The European Renal Best Practice (ERBP) Advisory Board and Canadian Society of Nephrology guidelines agree with KDIGO about whether and when to start ESA therapy in dialysis patients (ERBP 2013; Moist 2013).

Several systematic reviews have investigated ESA treatment for anaemia in patients with CKD and ESKD evaluating haemoglobin level, energy and physical function, fatigue, left ventricular mass index and mortality (Johansen 2010; Johansen 2012; Palmer 2010; Parfrey 2009; Vinhas 2012), but to date, a systematic review on the benefits and harms of early (haemoglobin < 11 g/dL but > 10 g/dL) versus delayed (haemoglobin ≤ 10 g/dL) ESA treatment for anaemia in dialysis patients with ESKD has not been published.