Background and objectives
Erythropoiesis-stimulating agents (ESAs) revolutionised the management of anaemia in chronic kidney disease (CKD) when introduced in the late 1980s. A range of ESA types, preparations and administration modalities now exist, with newer agents requiring less frequent administration. Though systematic reviews and meta-analyses have been published in adults, no systematic review has been conducted investigating ESAs in children.
Methods
The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement for the conduct of systematic reviews was used. All available literature on outcomes relating to ESAs in children with CKD was sought. A search of MEDLINE, CINAHL and EMBASE databases were conducted by two independent reviewers.
Inclusion criteria were: published trials in English; children with chronic and end-stage kidney disease; use of any ESA studied against any outcome measure. An assessment of risk of bias was carried out on all included randomised trials using the criteria from the Cochrane handbook for systematic reviews of interventions. Two tables were used for data extraction for randomised and observational studies. Study type, participants, inclusion criteria, case characteristics, follow up duration, ESA type and dosage, interventions and outcomes were extracted by one author.
Results
Of 965 identified articles, 58 were included covering 54 cohorts. 6 were randomised trials and 48 were observational studies. 38 studies assessed the efficacy of recombinant human erythropoietin (rHuEPO), 11 of darbepoetin (DA), and 3 of continuous erythropoietin receptor activator (CERA), with 6 studies appraising secondary outcome measures exclusively. Recruitment to studies was a consistent challenge. The commonest adverse effect was hypertension, though confounding effects often limited direct correlation. Two large cohort studies demonstrated a higher hazard of death independently associated with high ESA dose. Secondary outcome measures included quality of life measures, growth and nutrition, exercise capacity, injection site pain, cardiovascular function, intelligent quotient (IQ), evoked potentials, and platelet function.
Conclusions
All ESA preparations and modes of administration were efficacious, with evidence of harm at higher doses. Evidence supports individualising treatments with strong consideration given to alternate treatments in patients who appear resistant to ESA therapy. Further research should focus on randomised trials comparing the efficacy of different preparations, treatment options in apparently ESA resistant cohorts and clarification of meaningful secondary outcomes to consolidate patient-relevant indices.