Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (studies in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at interventions for the treatment of ESA‐resistant anaemia in people with ESKD were included in our review.

Types of participants

• Adults and children with ESKD (chronic kidney disease (CKD) stage 5 or pre‐dialysis) or those receiving dialysis (either haemodialysis or peritoneal dialysis).

• Adults and children with ESKD receiving any type of ESA for anaemia (anaemia defined as haemoglobin < 110 g/L or as defined by the investigators).

• Evidence of ESA resistance, defined as failure to achieve or maintain target range haemoglobin/haematocrit levels in spite of appropriate ESA doses (erythropoietin ≥ 450 U/kg/wk intravenous administration or ≥ 300 U/kg/wk for subcutaneous administration or darbepoetin ≥ 1.5 µg/kg/wk) (KDOQI 2001; Locatelli 2004). This inclusion criterion was amended after publication of the protocol of this systematic review because only one eligible study was found. Extended inclusion criteria were studies that defined ESA‐hyporesponsive state as failure to achieve or maintain target haemoglobin/haematocrit in spite of the following doses of the ESA: erythropoietin dosage ≥ 300 and ≥150 U/kg/wk for IV administration; or ≥ 200 and ≥100 U/kg/wk for subcutaneous administration; or darbepoetin dosage ≥ 1.0 µg/kg/wk).

• All known causes of ESA‐resistance (such as iron deficiency, vitamin B₁₂ deficiency, folate deficiency, infection, chronic inflammatory state, neoplasia, severe hyperparathyroidism, aluminium intoxication, inadequate dialysis, myelosuppressive agents, haemoglobinopathies, myelodysplasia and antibody‐mediated pure red cell aplasia) must have been ruled out.

• Studies performed in kidney transplant recipients were excluded.

Types of interventions

Any potential intervention used to treat ESA‐resistance, such as L‐carnitine, ascorbic acid, oxpentifylline, androgens, and statins, were included in this review.

Types of outcome measures

• All‐cause mortality

• Cardiovascular mortality

• Non‐fatal cardiovascular events

• Number of patients achieving target haemoglobin/haematocrit

• Difference or changes in haemoglobin or haematocrit between intervention and control groups at study end

• Difference or changes in ESA dose between intervention and control groups at study end

• Blood transfusion requirements

• Quality of life

• Hospitalisation

• Any reported adverse events

• Differences or changes in inflammatory biomarkers between intervention and control groups at study end

• Differences or changes in biomarkers of oxidative stress between intervention and control groups at study end.

Electronic searches

We searched the Cochrane Renal Group's specialised register 18th March 2013 through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from:

1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

2. Weekly searches of MEDLINE OVID SP

3. Handsearching of renal‐related journals and the proceedings of major renal conferences

4. Searching of the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected renal journals

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the specialised register are identified through search strategies for CENTRAL, MEDLINE and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the specialised register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of clinical practice guidelines, review articles and relevant studies.

2. Relevant missing or incomplete or unpublished data from the clinical studies were requested from the respective investigators/ authors by written correspondence.

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies relevant to the review. Titles and abstracts were screened independently by three authors, who discarded studies that were not applicable. However, studies and reviews that potentially included relevant data or study information were retained initially. The same three authors independently assessed retrieved abstracts, and if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals was to be translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions, these data were used. Any discrepancies between published versions was to be highlighted. Disagreements were resolved by consensus.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

  • Participants and personnel

  • Outcome assessors

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (all‐cause mortality, cardiovascular mortality, non‐fatal cardiovascular events, number of patients achieving haemoglobin/haematocrit targets, number of patients requiring hospitalisation, number of patients requiring blood transfusions, number of patients with medication‐related adverse effects), results were expressed as risk ratios (RR) with 95% confidence intervals (CI). For continuous data (haemoglobin, haematocrit, iron studies, ESA dosage, iron dosage, hospitalisation days, quality of life scores, inflammatory biomarkers, biomarkers of oxidative stress), results were expressed as mean difference (MD).

Dealing with missing data

We planned that any further information required from the original author was to be requested by written correspondence, and any relevant information obtained was be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat (ITT), as‐treated and per‐protocol (PP) population was performed.

Assessment of heterogeneity

Heterogeneity was to be analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Data synthesis

Data were to be pooled using the random‐effects model.