Intervention Review

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Interventions for erythropoietin-resistant anaemia in dialysis patients

  1. Sunil V Badve1,*,
  2. Elaine M Beller2,
  3. Alan Cass3,
  4. Daniel P Francis4,
  5. Carmel Hawley1,
  6. Iain C Macdougall5,
  7. Vlado Perkovic3,
  8. David W Johnson1

Editorial Group: Cochrane Renal Group

Published Online: 26 AUG 2013

Assessed as up-to-date: 4 APR 2013

DOI: 10.1002/14651858.CD006861.pub3


How to Cite

Badve SV, Beller EM, Cass A, Francis DP, Hawley C, Macdougall IC, Perkovic V, Johnson DW. Interventions for erythropoietin-resistant anaemia in dialysis patients. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006861. DOI: 10.1002/14651858.CD006861.pub3.

Author Information

  1. 1

    Princess Alexandra Hospital, Department of Nephrology, Woolloongabba, QLD, Australia

  2. 2

    Bond University, Faculty of Health Sciences and Medicine, Gold Coast, QLD, Australia

  3. 3

    The George Institute for Global Health, Renal and Metabolic Division, Camperdown, NSW, Australia

  4. 4

    Queensland Health, Central Regional Services, Division of the CHO, Stafford DC, QLD, Australia

  5. 5

    King's College Hospital, Renal Unit, London, UK

*Sunil V Badve, Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia. sunil_badve@health.qld.gov.au.

Publication History

  1. Publication Status: New
  2. Published Online: 26 AUG 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Description of the condition

Erythropoiesis-stimulating agents (ESAs) are perhaps the most rigorously tested group of drugs in nephrology. Since the introduction of ESAs, there have been substantial reductions in blood transfusion requirements among patients living with chronic kidney disease (CKD) (Eschbach 1989).

A systematic review of 14 randomised controlled and uncontrolled trials in pre-dialysis CKD patients demonstrated that treatment of anaemia with ESAs improved energy levels and physical function (Gandra 2010). Unfortunately, a considerable proportion of these patients exhibited suboptimal haematologic response to ESA (Benz 1999; Valderrabano 1996).

There are several known causes of suboptimal response to ESA. These include deficiencies in iron, vitamin B12, and folate; infection, chronic inflammatory state, neoplasia, severe hyperparathyroidism, aluminium intoxication, inadequate dialysis, myelosuppressive agents, haemoglobinopathies, myelodysplasia and antibody-mediated pure red cell aplasia (Macdougall 2002). However, after excluding these conditions it was found that about 10% of patients exhibit ESA-resistant anaemia, and these people have greatly increased rates of morbidity and mortality (Kausz 2005; Macdougall 2002; Zhang 2004).

ESA treatment used to target high haemoglobin levels in people with CKD is associated with deleterious (Phrommintikul 2007) or neutral (Palmer 2010) impacts on survival and increased risks of stroke, vascular access thrombosis and hypertension without any reduction in cardiovascular events (Palmer 2010; Phrommintikul 2007).

Although RCTs and systematic reviews consistently show more harm than benefit associated with higher haemoglobin targets for ESA treatment (Besarab 1998; Palmer 2010; Pfeffer 2009; Phrommintikul 2007; Singh 2006), secondary analyses of RCTs and observational studies have demonstrated that poor response to ESA treatment rather than achieved high haemoglobin, may be responsible for the observed suboptimal outcomes in people with CKD (Kilpatrick 2008; Messana 2009; Regidor 2006; Solomon 2010; Szczech 2008).

These studies also showed that patients who required higher doses of ESA experienced increased mortality at any haemoglobin level, and that patients who achieve target haemoglobin levels had better outcomes than those who did not (Badve 2011). Therefore, therapies targeting ESA resistance could be a promising treatment strategy in CKD anaemia management.

 

Description of the intervention

Although there is no effective treatment for patients with ESA-resistant anaemia at present, a number of interventions such as L-carnitine, ascorbic acid, oxpentifylline, androgens and statins have been investigated.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

This review looked at the benefits and harms of any intervention used in the treatment of ESA-resistant anaemia in people with end-stage kidney disease (ESKD) who were receiving dialysis.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Criteria for considering studies for this review

 

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.

 

Search methods for identification of studies

 

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.

 

Data collection and analysis

 

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.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Description of studies

 

Results of the search

We identified 533 abstracts using the search strategy described (Figure 1). After screening titles and abstracts, 99 reports were selected for full text review. Only two studies (Attallah 2006; Ayli 2004) met our inclusion criteria, and of these, one investigated our extended inclusion criterion of ESA hyporesponsive state (Ayli 2004).

 FigureFigure 1. The PRISMA flow chart showing selection of studies

We considered inclusion of a study that applied our extended inclusion criterion of ESA-hyporesponsive state (Sezer 2002). In this study, participants in both arms received the investigational drug (vitamin C) in the first study phase (eight weeks). Non-responders were excluded at the end of the first phase. During the second phase, remaining participants were randomised to receive either the investigational drug at a reduced frequency or no study drug for another eight weeks. Since the investigators did not define 'non-responder', and there was a strong possibility of carry over effect of vitamin C administered before randomisation, the study was excluded from this systematic review.

 

Included studies

Two studies met our inclusion criteria.

  • Attallah 2006 enrolled 42 haemodialysis patients and compared IV vitamin C given at each dialysis session to no treatment.
  • Ayli 2004 enrolled 48 haemodialysis patients and compared high-flux versus low-flux dialysis membranes

 

Excluded studies

We excluded 68 studies after full-text review: six were not randomised; 58 included participants who did not have ESA resistance; two included iron deficient participants who lacked true ESA resistance; and two studies did not use ESA in the control arm.

 

Risk of bias in included studies

 

Allocation

Allocation concealment was unclear in both included studies (Attallah 2006; Ayli 2004).

 

Blinding

It was unclear if in Attallah 2006, an open-label study, outcome assessors were blinded. Likewise, blinding of participants, investigators or outcome assessors in Ayli 2004 was also unclear.

 

Incomplete outcome data

All participants were followed for the entire study period and accounted for in both studies. Attrition bias arising from incomplete outcome reporting was deemed to be low risk.

 

Selective reporting

Neither study reported proportions of participants in each study arm who achieved haemoglobin target levels. The risk of reporting bias in both was therefore unclear.

 

Other potential sources of bias

Both studies were judged to be at high risk of other potential sources of bias due to single-centre study design and exclusion of patients on peritoneal dialysis.

 

Effects of interventions

Treatments differed in the interventional arms of Attallah 2006 and Ayli 2004 (vitamin C and high-flux dialyser). Therefore, data were not combined and results are presented separately.

 

Clinical outcomes

 

All-cause and cardiovascular mortality

No deaths were reported in either study.

 

Non-fatal cardiovascular events

Attallah 2006 reported no significant difference in the risk of non-fatal cardiovascular events between study arms ( Analysis 1.1: RR 0.79, 95% CI 0.20 to 3.09).

Ayli 2004 did not report non-fatal cardiovascular events.

 

Participants achieving target haemoglobin or haematocrit

Neither study reported the proportions of participants who achieved target haemoglobin or haematocrit levels.

 

Requirement of blood transfusions

Attallah 2006 reported no participants included in the final analysis required blood transfusion. However, one participant from the control group was excluded from the final analysis because of the need for a blood transfusion due to a significant upper gastrointestinal bleed.

Ayli 2004 did not report need for blood transfusion.

 

Hospitalisations

Attallah 2006 reported no significant difference in the risk of hospitalisations between the groups ( Analysis 1.2: RR 0.96, 95% CI 0.56 to 1.66).

Ayli 2004 did not report hospitalisations.

 

Medication-related adverse events

Attallah 2006 reported there were no adverse events noted in either group. Ayli 2004 did not report adverse events.

 

Haematology and biochemistry results

 

Haemoglobin

Both studies reported significantly higher haemoglobin levels in the treatment groups compared to the control groups ( Analysis 2.1.1: MD 0.9 g/dL, 95% CI 0.38 to 1.42; Attallah 2006); ( Analysis 2.1.2: MD 1.9 g/dL, 95% CI 1.64 to 2.16; Ayli 2004).

 

Haematocrit

Attallah 2006 did not report data on participants' haematocrit levels. Ayli 2004 reported that among interventional arm participants haematocrit was significantly higher than those in the control arm ( Analysis 2.2: MD 6.8%, 95% CI 5.67 to 7.93).

 

Transferin saturation (TSAT)

Attallah 2006 reported that TSAT was significantly higher in interventional than control arm participants ( Analysis 2.3.1: MD 8.00%, 95% CI 6.22 to 9.78). There was no significant difference in TSAT between study arms reported by Ayli 2004 ( Analysis 2.3.2: MD 1.30%, 95% CI -3.99 to 6.59).

 

Ferritin

Attallah 2006 reported that ferritin was significantly higher among interventional than control arm participants ( Analysis 2.4.1: MD 8.00 ng/mL, 95% CI -85.51 to 101.51). There was no significant difference between study arms reported by Ayli 2004 ( Analysis 2.4.2: MD -3.00 ng/mL, 95% CI -43.46 to 37.46).

 

Haemoglobin content in reticulocytes (CHr)

Attallah 2006 reported that CHr was significantly higher in interventional than control arm participants ( Analysis 2.5: MD 0.90 pg, 95% CI 0.40 to 1.40). Ayli 2004 did not report CHr data.

 

Inflammatory biomarkers: C-reactive protein

Attallah 2006 reported C-reactive protein was significantly lower in vitamin C group compared to the control group ( Analysis 2.6.1: MD -1.20 mg/dL, 95% CI -1.69 to -0.71). There was no significant difference between study arms in C-reactive protein reported by Ayli 2004 ( Analysis 2.6.2: MD -0.4 mg/dL, 95% CI -3.0 to 2.2).

 

Markers of oxidative stress

Neither Attallah 2006 nor Ayli 2004 reported markers of oxidative stress.

 

ESA and intravenous iron doses

 

ESA dose

Attallah 2006 reported ESA was significantly lower in vitamin c group compared to the control group ( Analysis 3.1: MD -18 U/kg/wk, 95% CI -35.62 to -0.38). Ayli 2004 did not report data on ESA dose.

 

Intravenous iron therapy dose

Attallah 2006 reported that there was no significant difference in intravenous iron therapy dose between the study arms ( Analysis 3.2: MD -0.20 mg/wk, 95% CI -16.15 to 15.75). Ayli 2004 did not report on intravenous iron therapy dose.

 

Other outcomes

 

Hospitalisation days

Neither Attallah 2006 nor Ayli 2004 reported numbers of hospitalisation days.

 

Quality of life scores

Neither Attallah 2006 nor Ayli 2004 reported quality of life scores.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

The results of this systematic review highlight the absence of adequately powered randomised controlled trials (RCT) examining the effect of various interventions to treat ESA hyporesponsiveness. We found that there was insufficient and inadequate evidence to recommend any intervention to ameliorate ESA-hyporesponsiveness.

We identified only one RCT that defined ESA-hyporesponsiveness as intravenous EPO dose ≥ 450 U/kg/wk (Attallah 2006). When inclusion criteria were extended to include subcutaneous EPO dose ≥ 200 U/kg/wk, another study, Ayli 2004, was found to be eligible for inclusion.

In relation to intravenous vitamin C therapy, Attallah 2006 demonstrated increases in haemoglobin, haemoglobin content in reticulocytes, and transferin saturation; and reductions in erythropoietin dose and C-reactive protein. Ayli 2004 reported that use of high-flux dialyser for six months was associated with improvement in haemoglobin, but there was no effect on C-reactive protein or iron studies. Both Attallah 2006 and Ayli 2004 were single-centre studies and included 42 and 48 participants respectively. The studies included only haemodialysis patients, and hence, results may not be generalisable to CKD patients not yet on dialysis, those on peritoneal dialysis, or in settings where patient populations differ.

There is no single widely accepted definition of ESA resistance. KDOQI has defined ESA resistance as failure to achieve haemoglobin 11 g/dL with ESA dose equivalent to epoetin greater than 500 IU/kg/wk (KDOQI 2006). Publication of KDIGO anaemia guidelines is expected this year. As yet, there have been no RCTs performed explicitly in patients with ESA resistance as defined by KDOQI.

In the Normal Haematocrit Cardiac Trial, more participants in the normal haematocrit group reached the primary endpoint (composite of death and non-fatal myocardial infarction) with mean erythropoietin doses of 440 IU/kg/wk, which is lower than the KDOQI definition (Besarab 1998). In the CHOIR trial, it was reported that ESA dose > 20,000 IU/wk was associated with increased risk of death, congestive heart failure, stroke, and myocardial infarction (Szczech 2008).

Several observational studies have suggested a linear association between ESA dose and adverse outcomes (Brookhart 2010; Messana 2009; Regidor 2006; Zhang 2004; Zhang 2009). There is substantial variability in the reporting of ESA dose, such as IU/kg/wk, IU/wk, or ESA dose normalised to haemoglobin level. Therefore, the current KDOQI definition of ESA resistance needs to be revised, and the new definition should be based on ESA-resistance index (ERI) rather than ESA dose to bring uniformity in reporting.

The revised inclusion criteria of the ongoing HERO Study are ESA-resistance index ≥ 1.0 IU/kg/wk/haemoglobin for epoetin-treated patients and ≥ 0.005 µg/kg/wk/g haemoglobin for darbepoetin-treated patients (Johnson 2008).  Table 1 presents current definitions of ESA resistance.

An emerging body of evidence indicates more harm than benefit from targeting higher haemoglobin levels with ESA therapy. Patients who needed higher doses of ESA experienced increased mortality at any haemoglobin level, and patients who achieved target haemoglobin levels had better outcomes than those who did not.

Further RCTs are needed urgently to consider the clinical impacts of therapies purported to reduce ESA resistance.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

 

Implications for practice

Based on two small, single-centre studies, there was inadequate evidence to recommend any intervention to ameliorate ESA-hyporesponsiveness.

 
Implications for research

Adequately powered multicentre RCTs involving a wide range of CKD patients receiving ESA therapy should be conducted as a priority. In addition to those on haemodialysis, future RCTs should include pre-dialysis CKD patients as well people receiving peritoneal dialysis.

Future studies should focus on true ESA responsiveness rather than a haemoglobin-targeted approach. Importantly, these studies should also include cost-effectiveness and economic analyses.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

The authors would like to acknowledge Narelle Willis and Ruth Mitchell from the Cochrane Renal Group for their assistance. The authors would also like to thank the referees for their editorial advice during the preparation of this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
Download statistical data

 
Comparison 1. Clinical outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Non-fatal cardiovascular events1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 2 Hospitalisations1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 2. Haematology and biochemistry results

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Haemoglobin2Mean Difference (IV, Random, 95% CI)Totals not selected

    1.1 Vitamin C versus control
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 High-flux versus low-flux dialyser
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 2 Haematocrit1Mean Difference (IV, Random, 95% CI)Totals not selected

 3 Transferin saturation (TSAT)2Mean Difference (IV, Random, 95% CI)Totals not selected

    3.1 Vitamin C versus control
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 High-flux versus low-flux dialyser
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 4 Ferritin2Mean Difference (IV, Random, 95% CI)Totals not selected

    4.1 Vitamin C versus control
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 High-flux versus low-flux dialyser
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 5 Haemoglobin content in reticulocytes (CHr)1Mean Difference (IV, Random, 95% CI)Totals not selected

 6 C-reactive protein2Mean Difference (IV, Random, 95% CI)Totals not selected

    6.1 Vitamin C versus control
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 High-flux versus low-flux dialyser
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. ESA and IV iron doses

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 EPO dose1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 IV Iron1Mean Difference (IV, Random, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Appendix 1. Electronic search strategies


DatabaseSearch terms

CENTRAL
  1. dialysis:ti,ab,kw
  2. (hemodia* or haemodia*):ti,ab,kw
  3. (hemofiltration or haemofiltration):ti,ab,kw
  4. (#1 OR #2 OR #3)
  5. an*emia:ti,ab,kw
  6. "iron overload":ti,ab,kw
  7. (#5 OR #6)
  8. erythropo*etin:ti,ab,kw
  9. (erythropo*esis next stimulating next agent*):ti,ab,kw
  10. (continuous next erythropo*esis next receptor next activator*):ti,ab,kw
  11. EPO:ti,ab,kw
  12. rhEPO:ti,ab,kw
  13. epo*etin:ti,ab,kw
  14. Eprex:ti,ab,kw
  15. Epogen:ti,ab,kw
  16. Procrit:ti,ab,kw
  17. darbepo*etin:ti,ab,kw
  18. aranesp:ti,ab,kw
  19. neorecormon:ti,ab,kw
  20. CERA:ti,ab,kw
  21. mircera:ti,ab,kw
  22. (#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21)
  23. (#4 AND #7 AND #22)

MEDLINE
  1. exp Renal Dialysis/
  2. dialysis.tw.
  3. (hemodialysis or haemodialysis).tw.
  4. (hemofiltration or haemofiltration).tw.
  5. (hemodiafiltration or haemodiafiltration).tw.
  6. or/1-5
  7. Anemia/
  8. Anemia,Refractory/
  9. Iron Overload/
  10. (an?emia or an?emic).tw.
  11. or/7-10
  12. exp Erythropoietin/
  13. erythropoiesis stimulating agent$.tw.
  14. erythropo?etin.tw.
  15. EPO.tw.
  16. rhEPO.tw.
  17. epo?etin.tw.
  18. Eprex.tw.
  19. Epogen.tw.
  20. Procrit.tw.
  21. darbepo?etin.tw.
  22. aranesp.tw.
  23. neorecormon.tw.
  24. continuous erythropo?esis receptor activator.tw.
  25. CERA.tw.
  26. Mircera.tw.
  27. or/12-26
  28. and/6, 11, 27

EMBASE
  1. Anemia/
  2. Refractory Anemia/
  3. Iron Overload/
  4. (an?emia or an?emic).tw.
  5. or/1-4
  6. Erythropoietin/
  7. Recombinant Erythropoietin/
  8. erythropo?esis stimulating agent$.tw.
  9. erythropo?etin.tw.
  10. EPO.tw.
  11. rhEPO.tw.
  12. epo?etin.tw.
  13. Eprex.tw.
  14. Epogen.tw.
  15. Procrit.tw.
  16. darbepo?etin.tw.
  17. aranesp.tw.
  18. neorecormon.tw.
  19. continuous erythropo?esis receptor activator.tw.
  20. CERA.tw.
  21. Mircera.tw.
  22. or/6-21
  23. exp Renal Replacement Therapy/
  24. dialysis.tw.
  25. (hemodialysis or haemodialysis).tw.
  26. (hemofiltration or haemofiltration).tw.
  27. (hemodiafiltration or haemodiafiltration).tw.
  28. or/23-27
  29. and/5, 22, 28



 

Appendix 2. Risk of bias assessment tool


Potential source of biasAssessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).

High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.

Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).

High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.
Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.
Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.

High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting
Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table
Low risk of bias: The study appears to be free of other sources of bias.

High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.

Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

  • Write the protocol: SB, DF, EB, CH, DJ, IM, AC, VP
  • Study selection: SB, CH, DJ
  • Extract data from studies: SB, DJ
  • Enter data into RevMan: SB, DJ
  • Data analysis: SB, DF, EB
  • Interpret the analysis: SB, DJ
  • Draft the final review: SB, DJ
  • Disagreement resolution: DF, EB, CH, IM, AC, VP
  • Update the review: SB, DJ

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

  • Dr Sunil V Badve, Elaine Beller and Daniel P Francis have no conflicts of interest to declare.
  • Associate Professor Carmel Hawley has received consulting fees from Amgen and Janssen-Cilag; research grants from Amgen, Roche and Janssen-Cilag; and speakers’ honoraria from Amgen.
  • Professor Alan Cass is the recipient of a NHMRC Senior Research Fellowship. He has received speaker's honoraria and research grants from Janssen-Cilag, Amgen and Roche.
  • Associate Professor Vlado Perkovic has received speakers’ honoraria from Roche and research grants from Johnson and Johnson Pharmaceutical Research & Development and Roche.
  • Professor Iain C. Macdougall has received consultant fees, research grants, and/or lecture fees from Amgen, Ortho biotech, Roche, Affymax, Takeda, Hospira, and Sandoz.
  • Professor David Johnson has received speakers' honoraria, consultancy fees and research grants from Janssen-Cilag, Amgen and Roche. He has received fees for organising education from Amgen and Janssen-Cilag. He has received consultancy fees from Pfizer. He is also the Principal Investigator in the HERO Trial, a randomised, double-blind, placebo-controlled trial of oxpentifylline in the treatment of erythropoietin stimulating agent hyporesponsiveness. Professor Alan Cass and Associate Professor Carmel Hawley are the members of the Trial Management Committee of the HERO trial.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Internal sources

  • Australasian Kidney Trials Network, School of Medicine, University of Queensland, Australia.
  • Princess Alexandra Hospital, Woolloongabba, QLD, Australia.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

In the protocol for this review, we had planned that one of our inclusion criteria would define ESA resistance. Evidence of ESA-resistance, defined as failure to achieve or maintain target range haemoglobin/haematocrit levels in spite of appropriate doses of the ESA (erythropoietin dose ≥ 450 U/kg/wk intravenous administration or ≥ 300 U/kg/wk for subcutaneous administration or darbepoetin dosage ≥ 1.5 µg/kg/wk) (KDOQI 2001; Locatelli 2004) was to be applied. This inclusion criterion was amended because only one eligible study was found.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Attallah 2006 {published data only}
  • Attallah N, Osman-Malik Y, Adams B, Frinak S, Besarab A. Effect of intravenous ascorbic acid in hemodialysis patients with erythropoietin-hyporesponsive anemia and hyperferritenemia [abstract]. Journal of the American Society of Nephrology 2005;16:488A.
  • Attallah N, Osman-Malik Y, Frinak S, Besarab A. Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. American Journal of Kidney Diseases 2006;47(4):644-54. [MEDLINE: 16564942]
Ayli 2004 {published data only}
  • Ayli D, Ayli M, Azak A, Yksel C, Kosmaz GP, Atilgan G, et al. The effect of high-flux hemodialysis on renal anemia. Journal of Nephrology 2004;17(5):701-6. [MEDLINE: 15593038]
  • Ayli M, Ayli D, Azak A, Yuksel C, Atilgan G, Dede F, et al. The effect of high-flux hemodialysis on dialysis-associated amyloidosis. Renal Failure 2005;27(1):31-4. [MEDLINE: 15717632]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Abe 2010 {published data only}
  • Abe M, Okada K, Maruyama T, Maruyama N, Soma M, Matsumoto K. Clinical effectiveness and safety evaluation of long-term pioglitazone treatment for erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis. Expert Opinion on Pharmacotherapy 2010;11(10):1611-20. [MEDLINE: 20540652]
Acchiardo 1989 {published data only}
  • Acchiardo SR, Quinn BP, Burk LB, Moore LW. Are high flux dialysis and erythropoietin treatment in a collision course?. ASAIO Transactions 1989;35(3):308-10. [MEDLINE: 2688711]
Aliev 1997 {published data only}
  • Aliev MA, Ismagilov RZ, Tsoy GM, Yusumbaeva AS. Influence of Eprex in combination with antihistamine drugs on correction of anemia in haemodialysis patients [abstract]. 34th Congress European Renal Association/European Dialysis and Transplantation Association; Geneva, Switzerland. 1997:236.
Andrulli 2010 {published data only}
  • Andrulli S, Di Filippo S, Manzoni C, Stefanelli L, Floridi A, Galli F, et al. Effect of synthetic vitamin E-bonded membrane on responsiveness to erythropoiesis-stimulating agents in hemodialysis patients: a pilot study. Nephron 2010;115(1):c82-9. [MEDLINE: 20215781]
Ballal 1991 {published data only}
  • Ballal SH, Domoto DT, Polack DC, Marciulonis P, Martin KJ. Androgens potentiate the effects of erythropoietin in the treatment of anemia of end-stage renal disease. American Journal of Kidney Diseases 1991;17(1):29-33. [MEDLINE: 1986567]
Barany 1998 {published data only}
  • Barany P. Treatment of anemia in hemodialysis patients to a normal hemoglobin concentration - results of an open randomized clinical trial of epoetin beta [abstract]. Journal of the American Society of Nephrology 1998;9:243A.
Berns 1992 {published data only}
  • Berns JS, Rudnick MR, Cohen RM. A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodialysis. Clinical Nephrology 1992;37(5):264-7. [MEDLINE: 1606777]
Brockenbrough 2006 {published data only}
  • Brockenbrough AT, Dittrich MO, Page ST, Smith T, Stivelman JC, Bremner WJ. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. American Journal of Kidney Diseases 2006;47(2):251-62. [MEDLINE: 16431254]
Buchwald 1977 {published data only}
Cao 2010 {published data only}
  • Cao W, Liu JH, Zhang H, Zhang L, Zhang LY, Pan MM. Effect of acupoint injection on erythropoietin resistance in patients with chronic renal failure. Zhongguo Zhenjiu [Chinese Acupuncture & Moxibustion] 2010;30(11):891-5. [MEDLINE: 21246842]
Caruso 1998 {published data only}
  • Caruso U, Leone L, Cravotto E, Nava D. Effects of L-carnitine on anemia in aged hemodialysis patients treated with recombinant human erythropoietin: A pilot study. Dialysis & Transplantation 1998;27(8):498-506. [EMBASE: 1998284168]
Cerulli 2000 {published data only}
  • The effect of hemodiafiltration with on-line endogenous reinfusion (on-line HFR) on anemia: design of a European, open, randomised, multicentre trial. European Collaborative Study. Journal of Nephrology 2000;13(1):34-42. [MEDLINE: 10720212]
Chan 2005 {published data only}
  • Chan D, Irish A, Croft KD, Dogra G. Effect of ascorbic acid supplementation on plasma isoprostanes in haemodialysis patients. Nephrology Dialysis Transplantation 2006;21(1):234-5. [MEDLINE: 16204285]
  • Chan D, Irish A, Dogra G. Efficacy and safety of oral compared with intravenous ascorbic acid in improving anaemia in erythropoietin hyporesponsive, iron overloaded, haemodialysis patients - a randomised open-label study [abstract]. Nephrology 2003;8 Suppl 3:A80-1.
  • Chan D, Irish A, Dogra G. Efficacy and safety of oral versus intravenous ascorbic acid for anaemia in haemodialysis patients. Nephrology 2005;10(4):336-40. [MEDLINE: 16109077]
Chen 2003 {published data only}
  • Chen WT, Lin YF, Yu FC, Kao WY, Huang WH, Yan HC. Effect of ascorbic acid administration in hemodialysis patients on in vitro oxidative stress parameters: influence of serum ferritin levels. American Journal of Kidney Diseases 2003;42(1):158-66. [MEDLINE: 12830468]
Cruz 2008 {published data only}
  • Cruz DN, De Cal M, Garzotto F, Brendolan A, Nalesso F, Corradi V, et al. Effect of vitamin E-coated dialysis membranes on anemia in patients with chronic kidney disease: an Italian multicenter study. International Journal of Artificial Organs 2008;31(6):545-52. [MEDLINE: 18609507]
Culleton 2007 {published data only}
  • Culleton BF, Walsh M, Klarenbach SW, Mortis G, Scott-Douglas N, Quinn RR, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA 2007;298(11):1291-9. [MEDLINE: 17878421]
  • Culleton BF, Walsh M, Klarenbach SW, Mortis G, Scott-Douglas N, Quinn RR, et al. Nocturnal hemodialysis lowers blood pressure and reduces left ventricular mass: results of a randomized controlled trial [abstract]. Journal of the American Society of Nephrology 2007;18(Abstracts):67A-8A.
  • Khangura J, Culleton BF, Manns BJ, Zhang J, Barnieh L, Walsh M, et al. Association between routine and standardized blood pressure measurements and left ventricular hypertrophy among patients on hemodialysis. BMC Nephrology 2010;11:13. [MEDLINE: 20576127]
  • Manns BJ, Klarenbach S, Walsh M, Quinn R, Tonelli M, Scott-Douglas N, et al. The impact of nocturnal hemodialysis on quality of life: results of a randomized controlled trial [abstract]. Journal of the American Society of Nephrology 2007;18(Abstracts):298A-9A.
  • Manns BJ, Walsh MW, Culleton BF, Hemmelgarn B, Tonelli M, Schorr M, et al. Nocturnal hemodialysis does not improve overall measures of quality of life compared to conventional hemodialysis. Kidney International 2009;75(5):542-9. [MEDLINE: 19109588]
  • Schorr M, Manns BJ, Culleton B, Walsh M, Klarenbach S, Tonelli M, et al. The effect of nocturnal and conventional hemodialysis on markers of nutritional status: results from a randomized trial. Journal of Renal Nutrition 2011;21(3):271-6. [MEDLINE: 20650654]
  • Walsh M, Manns B, Tonelli M, Quinn R, Culleton B. Description of a randomized controlled trial on the effects of nocturnal hemodialysis on left ventricular hypertrophy compared to conventional hemodialysis [abstract]. Journal of the American Society of Nephrology 2005;16:734A-5A.
  • Walsh M, Manns BJ, Klarenbach S, Quinn R, Tonelli M, Culleton BF. The effects of nocturnal hemodialysis compared to conventional hemodialysis on change in left ventricular mass: rationale and study design of a randomized controlled pilot study. BMC Nephrology 2006;7:2. [MEDLINE: 16504054]
  • Walsh M, Manns BJ, Klarenbach S, Tonelli M, Hemmelgarn B, Culleton B. The effects of nocturnal compared with conventional hemodialysis on mineral metabolism: a randomized-controlled trial. Hemodialysis International 2010;14(2):174-81. [MEDLINE: 20041960]
Deira 2003 {published data only}
  • Deira J, Diego J, Martinez R, Oyarbide A, Gonzalez A, Diaz H, et al. Comparative study of intravenous ascorbic acid versus low-dose desferroxamine in patients on hemodialysis with hyperferritinemia. Journal of Nephrology 2003;16(5):703-9. [MEDLINE: 14733417]
Di Iorio 2003 {published data only}
  • Di Iorio BR, Bellizzi V, Minutolo R, De Nicola L, Iodice C, Conte G. Supplemented very low-protein diet in advanced CRF: is it money saving?. Kidney International 2004;65(2):742. [MEDLINE: 14717953]
  • Di Iorio BR, Minutolo R, De Nicola L, Bellizzi V, Catapano F, Iodice C, et al. Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure. Kidney International 2003;64(5):1822-8. [MEDLINE: 14531817]
ECAP Study 2006 {published data only}
  • Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrology Dialysis Transplantation 2007;22(3):794-800. [MEDLINE: 17210593]
  • Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and risk factors for erythropoetin hyporesponsiveness in chronic kidney disease: analysis of the ECAP study [abstract]. Journal of the American Society of Nephrology 2004;15(Oct):141A.
  • Rossert J, Levin A, Roger S, Horl W, Gassman-Mayer C, Frei D, et al. Effect of early correction of anemia on the progression of chronic kidney disease: final results ECAP study [abstract]. Journal of the American Society of Nephrology 2004;15(Oct):546A.
  • Rossert J, Levin A, Roger SD, Horl WH, Fouqueray B, Gassmann-Mayer C, et al. Effect of early correction of anemia on the progression of CKD. American Journal of Kidney Diseases 2006;47(5):738-50. [MEDLINE: 16632012]
  • Rossert J, Roger S, Levin A, Horl W, McClellan W. Effect on early correction of anemia on the progression of chronic kidney disease (ECAP) [abstract]. Journal of the American Society of Nephrology 2003;14(Nov):811A.
Eiselt 2000 {published data only}
Garcia Cortes 1999 {published data only}
  • Garcia Cortes MJ, Sanchez Pearles MC, Perez del Barrio MP, Borrego Utiel FJ, Liebana A, Borrego Hinojosa J, et al. Effects of biocompatible membranes on uremic anemia in hemodialysis patients [abstract]. Nephrology Dialysis Transplantation 1999;14(9):A260.
  • Garcia Cortes MJ, Sanchez Perales MC, Liebana A, Gil JM, Borrego FJ, Borrego J, et al. Beneficial effect of AN69 membranes on anemia in hemodialyzed patients. Nefrologia 2001;21(4):370-5. [MEDLINE: 11816513]
Garrote 2009 {published data only}
  • Garrote N, Guinsburg M, Garcia L, Boubee S, Moretto H, Canale R, et al. Vitamin C improves HB levels and reduce EPO resistance in hemodialysis (HD) patients with functional iron deficiency (FID). A randomized, open label, controlled multicentric trial [abstract SA778]. World Congress of Nephrology; 2009 May 22-26; Milan (Italy). 2009.
Gastaldello 1995 {published data only}
  • Gastaldello K, Vereerstraeten A, Nzame-Nze T, Vanherweghem JL, Tielemans C. Resistance to erythropoietin in iron-overloaded haemodialysis patients can be overcome by ascorbic acid administration. Nephrology Dialysis Transplantation 1995;10(Suppl 6):44-7. [MEDLINE: 8524494]
Gaughan 1997 {published data only}
  • Gaughan WJ, Liss KA, Dunn SR, Mangold AM, Buhsmer JP, Michael B, et al. A 6-month study of low-dose recombinant human erythropoietin alone and in combination with androgens for the treatment of anemia in chronic hemodialysis patients. American Journal of Kidney Diseases 1997;30(4):495-500. [MEDLINE: 9328363]
  • Liss KA, Gaughan WJ, Dunn SR, Michael B, Goldman JM, Armenti VT, et al. A six month study of low-dose recombinant human erythropoietin alone and in combination with androgen for the treatment of anemia in chronic hemodialysis patients [abstract]. Journal of the American Society of Nephrology 1996;7(9):1490.
Giancaspro 2000 {published data only}
  • Giancaspro V, Nuzziello M, Pallotta G, Sacchetti A, Petrarulo F. Intravenous ascorbic acid in hemodialysis patients with functional iron deficiency: a clinical trial. Journal of Nephrology 2000;13(6):444-9. [MEDLINE: 11132761]
Hakemi 2005 {published data only}
  • Hakemi MS, Ganji MR, Najafi I, Shekarchi M. Intravenous ascorbic acid in comparison to intravenous iron in erythropoietin resistant anemia with iron overload in hemodialysis patients [abstract]. Nephrology 2005;10(Suppl):A314.
Hsu 2004 {published data only}
  • Hsu PY, Lin CL, Yu CC, Chien CC, Hsiau TG, Sun TH, et al. Ultrapure dialysate improves iron utilization and erythropoietin response in chronic hemodialysis patients - a prospective cross-over study. Journal of Nephrology 2004;17(5):693-700. [MEDLINE: 15593037]
Hung 2005 {published data only}
  • Hung SC, Tung TY, Yang CS, Tarng DC. High-calorie supplementation increases serum leptin levels and improves response to rHuEPO in long-term hemodialysis patients. American Journal of Kidney Diseases 2005;45(6):1073-83. [MEDLINE: 15957137]
Imada 2001 {published data only}
  • Imada A, Yoshimoto S, Ohno T, Takahashi K, Imada T, Iida N. Effect of Vitamin C on recombinant human erythropoietin refractory anemia in patients with chronic hemodialysis [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):332A.
ISRCTN96315193 {published data only}
  • Comparison of the effect of erythropoietin, L-carnitine and erythropoietin plus L-carnitine in correction of anemia in chronic hemodialysis patients. http://www.controlled-trials.com/ISRCTN96315193/ISRCTN96315193 (accessed 11th March 2013).
Jacobs 2006 {published data only}
Janssen 1995 {published data only}
  • Janssen MJ, van der Kuy A, ter Wee PM, van Boven WP. Calcium acetate versus calcium carbonate and erythropoietin dosages in haemodialysis patients. Nephrology Dialysis Transplantation 1995;10(12):2321-4. [MEDLINE: 8808233]
Kato 2000 {published data only}
Keven 2003 {published data only}
  • Deicher R, Horl WH. Vitamin C for hyporesponsiveness to EPO: a cure for all?. American Journal of Kidney Diseases 2003;42(4):848-9. [MEDLINE: 14520639]
  • Keven K, Kutlay S, Nergizoglu G, Duman N, Erturk S. The effect of intravenous vitamin C on erythropoietin response in haemodialysis patients [abstract]. Nephrology Dialysis Transplantation 2002;17(Suppl 1):229.
  • Keven K, Kutlay S, Nergizoglu G, Erturk S. Randomized, crossover study of the effect of vitamin C on EPO response in hemodialysis patients. American Journal of Kidney Diseases 2003;41(6):1233-9. [MEDLINE: 12776276]
  • Keven K, Kutlay S, Nergizoglu G, Erturk S. The effect of Vitamin C on erythropoietin response in hemodialysis patients [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):357A-8A.
Klarenbach 2002 {published data only}
  • Klarenbach S, Heidenheim AP, Leitch R, Lindsay RM, Daily/Nocturnal Dialysis Study Group. Reduced requirement for erythropoietin with quotidian hemodialysis therapy. ASAIO Journal 2002;48(1):57-61. [MEDLINE: 11814098]
Kletzmayr 1999 {published data only}
  • Kletzmayr J, Mayer G, Legenstein E, Heinz-Peer G, Leitha T, Horl WH, et al. Anemia and carnitine supplementation in hemodialyzed patients. Kidney International - Supplement 1999;55(Suppl 69):S93-S106. [MEDLINE: 10084293]
Koronis 2000 {published data only}
  • Koronis C, Makris F, Stavroulaki E, Lambropoulou A, Orthopoulos V. Combination of low-dose recombinant human erythropoietin with androgens for the treatment of anaemia in hemodialysis patients [abstract]. 37th Congress. European Renal Association. European Dialysis and Transplantation Association. European Kidney Research Organisation; Nice (France). 2000:235.
Labonia 1995 {published data only}
Lee 2001 {published data only}
  • Lee M, Ahn S, Song J. Effects of adjuvant androgen on anemia and nutritional parameters in chronic hemodialysis patients using low-dose recombinant human erythropoietin [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):358A-9A.
Locatelli 1999 {published data only}
  • Locatelli F, Andrulli S, Del Vecchio L. Anemia of hemodialysis patients: evaluation of the effect of BK-F polymethylmethacrylate membrane. Contributions to Nephrology 1999;125:173-81. [MEDLINE: 9895439]
Locatelli 2000 {published data only}
Malegos 2000 {published data only}
  • Malegos I, Kaloheretis P, Drouzas A, Papadakis I. Does haemodialysis membrane's biocompatibility affect recombinant human erythropoietin (rHuEPO) effect on the anemia of hemodialyzed patients? [abstract]. Nephrology Dialysis Transplantation 2000;15(9):A156.
Miyahara 1990 {published data only}
  • Miyahara S, Motomori T, Miyazaki F, Noda S, Eto K, Nakamura Y, et al. Clinical studies of mepitiostane for treatment of anemia associated with chronic renal failure. Kiso to Rinsho (The Clinical Report) 1990;24(5):2963-8.
Mydlík 2003 {published data only}
Nakamoto 2008 {published data only}
Navarro 2002 {published data only}
  • Navarro JF, Mora C, Macia M, Chahin J, Gallego E, Mendez ML, et al. Effects of androgen therapy on hematologic and nutritional parameters in elderly peritoneal dialysis patients [abstract]. International Urology & Nephrology 2001;33(4):715-6.
  • Navarro JF, Mora C, Macia ML, Gallego E, Chahin J, Mendez ML, et al. Prospective comparison between rHuEPO and androgens in CAPD patients: impact on hematologic and nutritional parameters [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):436A.
  • Navarro JF,  Mora C,  Macía M,  García J. Randomized prospective comparison between erythropoietin and androgens in CAPD patients. Kidney International 2002;61(4):1537-44. [MEDLINE: 11918762]
Odabas 2003 {published data only}
  • Odabas AR, Cetinkaya R, Selcuk Y, Keles S, Bilen H. The effect of high dose losartan on erythropoietin resistance in patients undergoing haemodialysis. Panminerva medica 2003;45(1):59-62. [MEDLINE: 12682621]
Ono 1992 {published data only}
Onoyama 1989 {published data only}
  • Onoyama K, Sanai T, Motomura K, Fujishima M. Worsening of anemia by angiotensin converting enzyme inhibitors and its prevention by antiestrogenic steroid in chronic hemodialysis patients. Journal of Cardiovascular Pharmacology 1989;13(Suppl 3):S27-S30. [MEDLINE: 2474097]
Opatrnì 1998 {published data only}
Panichi 2011 {published data only}
  • Panichi V, Barattini M, Angelini D, Petrone I, Ferrandello FP, Grazi G, et al. A vitamin E-coated polysulfone membrane reduces inflammatory markers and EPO requirement in haemodialysis patients [abstract SA413]. World Congress of Nephrology; 2009 May 22-26; Milan (Italy). 2009.
  • Panichi V, Rosati A, Paoletti S, Ferrandello P, Migliori M, Beati S, et al. A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial. Blood Purification 2011;32(1):7-14. [MEDLINE: 21242686]
Rao 2003 {published data only}
Richardson 2003 {published data only}
  • Richardson D, Lindley E, Bartlett C, Will EJ. Biocompatibility and erythropoiesis: - a randomised controlled, single center study of modified cellulose and polysulfone dialysers in a large hemodialysis cohort (n = 177) [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):240A.
  • Richardson D, Lindley EJ, Bartlett C, Will EJ. A randomized, controlled study of the consequences of hemodialysis membrane composition on erythropoietic response. American Journal of Kidney Diseases 2003;42(3):551-60. [MEDLINE: 12955684]
Saxena 1997 {published data only}
  • Saxena S, Dash SC, Tiwari SC, Agarwal SK, Jain PK, Aslam J. Effect of nandrolone deconoate on response to low dose erythropoietin (EPO) in anemia of end stage renal disease (ESRD) patients on maintenance hemodialysis (MHD) [abstract]. Nephrology 1997;3(Suppl 1):S310.
Sezer 2002 {published data only}
Shahrbanoo 2008 {published data only}
  • Shahrbanoo K, Taziki O. Effect of intravenous ascorbic acid in hemodialysis patients with anemia and hyperferritinemia. Saudi Journal of Kidney Diseases & Transplantation 2008;19(6):933-6. [MEDLINE: 18974579]
Sheashaa 2005 {published data only}
  • Sheashaa H, Abdel-Razek W, El Husseini A, Selim A, Hassan N, Abbas T, et al. Use of nandrolone decanoate as an adjuvant for erythropoietin dose reduction in treating anemia in patients on hemodialysis. Nephron 2005;99(4):c102-6. [MEDLINE: 15703460]
Sorge-Haedicke 2001 {published data only}
  • Sorge-Haedicke B, Goncalves-Marques M, Loew L, Samizadeh A. Routine intravenous l-carnitine-supplementation does not reduce erythropoietin (RH-EPO)- requirement in chronic hemodialysis (CHD) patients (P) with renal anemia (RA). Nephrology Dialysis Transplantation 2001;16(6):A135.
Taji 2004 {published data only}
  • Taji Y, Morimoto T, Okada K, Fukuhara S, Fukui T, Kuwahara T. Effects of intravenous ascorbic acid on erythropoiesis and quality of life in unselected hemodialysis patients. Journal of Nephrology 2004;17(4):537-43. [MEDLINE: 15372416]
Tarng 1998 {published data only}
  • Tarng DC, Huang TP. A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload. Nephrology Dialysis Transplantation 1998;13(11):2867-72. [MEDLINE: 9829492]
Tarng 1999 {published data only}
  • Tarng DC, Wei YH, Huang TP, Kuo BI, Yang WC. Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Kidney International 1999;55(6):2477-86. [MEDLINE: 10354297]
Tarng 2004 {published data only}
  • Tarng DC, Hung SC, Huang TP. Effect of intravenous ascorbic acid medication on serum levels of soluble transferrin receptor in hemodialysis patients. Journal of the American Society of Nephrology 2004;15(9):2486-93. [MEDLINE: 15339999]
Ursea 1995 {published data only}
  • Ursea N, Capsa D. Faster improvement of the anemia in chronic hemodialysed patients with combined treatment with erythropoetin and essential amino acids ketoanalogues [abstract]. Nephrology Dialysis Transplantation 1995;10(6):1051.
Usberti 2002a {published data only}
  • Usberti M, Gerardi G, Bufano G, Tira P, Micheli A, Albertini A, et al. Effects of erythropoietin and vitamin E-modified membrane on plasma oxidative stress markers and anemia of hemodialyzed patients. American Journal of Kidney Diseases 2002;40(3):590-9. [MEDLINE: 12200812]
Usberti 2002b {published data only}
  • Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, et al. Effects of a vitamin E-bonded membrane and of glutathione on anemia and erythropoietin requirements in hemodialysis patients. Journal of Nephrology 2002;15(5):558-64. [MEDLINE: 12455724]
Vaslaki 2006 {published data only}
  • Vaslaki L, Berta K, Ladanyi E, Pethoe F, Karatson A, Misz M, et al. Less need for erythropoietin in on-line haemodiafiltration compared to haemodialysis [abstract]. Nephrology Dialysis Transplantation 2005;20(Suppl 5):v336.
  • Vaslaki L, Major L, Berta K, Karatson A, Misz M, Pethoe F, et al. On-line haemodiafiltration versus haemodialysis: stable haematocrit with less erythropoietin and improvement of other relevant blood parameters. Blood Purification 2006;24(2):163-73. [MEDLINE: 16352871]
Wang 2000 {published data only}
  • Wang M-C, Huang J-J, Liao L-H, Ruaan M-K, Sung J-M, Lan R-R. Effect of high-dose folic acid on hemodialysis patients with poor erythropoietin response. Dialysis & Transplantation 2000;29(11):710-7. [EMBASE: 2000401292]
Yang 2006 {published data only}

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Johnson 2008 {published data only}
  • Johnson DW, Hawley CM, Rosser B, Beller E, Thompson C, Fassett RG, et al. Oxpentifylline versus placebo in the treatment of erythropoietin-resistant anaemia: a randomized controlled trial. BMC Nephrology 2008;9:8. [MEDLINE: 18671885]
NCT01526798 {published data only}
  • Improvement of EPO-resistance in hemodialysis patients with chronic inflammation by high cut-off hemodialysis (CIEPO-PILOT). http://www.clinicaltrials.gov/ct2/results?term=NCT01526798 (accessed 18th March 2013).

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to ongoing studies
  20. Additional references
  21. References to other published versions of this review
Badve 2011
Benz 1999
  • Benz RL, Pressman MR, Hovick ET, Peterson DD. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). American Journal of Kidney Diseases 1999;34(6):1089-95. [MEDLINE: 10585319]
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