American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1089-1097, December 2009

Ascorbic Acid for Anemia Management in Hemodialysis Patients: A Systematic Review and Meta-analysis

  • Vinay Deved, MD

      Affiliations

    • Department of Medicine, University of Calgary, Calgary, Alberta, Canada
    • Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
    • ,
  • Penelope Poyah, MD

      Affiliations

    • Department of Medicine, Dalhouise University, Halifax, Nova Scotia, Canada
    • ,
  • Matthew T. James, MD

      Affiliations

    • Department of Medicine, University of Calgary, Calgary, Alberta, Canada
    • Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
    • ,
  • Marcello Tonelli, MD, SM

      Affiliations

    • Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
    • ,
  • Braden J. Manns, MD, MSc

      Affiliations

    • Department of Medicine, University of Calgary, Calgary, Alberta, Canada
    • Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
    • ,
  • Michael Walsh, MD

      Affiliations

    • Department of Medicine, University of Calgary, Calgary, Alberta, Canada
    • Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
    • ,
  • Brenda R. Hemmelgarn, MD, PhD

      Affiliations

    • Department of Medicine, University of Calgary, Calgary, Alberta, Canada
    • Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
    • Corresponding Author InformationAddress correspondence to Brenda R. Hemmelgarn, MD, PhD, Division of Nephrology, Foothills Medical Centre, 1403 29th St NW, Calgary, Alberta, Canada T2N 2T9
    • ,
  • Alberta Kidney Disease Network

Received 23 March 2009; accepted 29 June 2009. published online 24 September 2009.

Article Outline

Background

Ascorbic acid is believed to improve anemia in patients with end-stage renal disease, but its overall effectiveness is unclear.

Study Design

Systematic review and meta-analysis.

Setting & Population

Adult hemodialysis patients.

Selection Criteria for Studies

Randomized clinical trials of ascorbic acid use in addition to standard anemia management.

Intervention

Ascorbic acid.

Outcomes

Weighted mean difference (WMD) for change in hemoglobin level, recombinant human erythropoietin (rHuEPO) dose, transferrin saturation and ferritin level and adverse events.

Results

Of 157 potentially relevant studies, 6 studies (n = 326 patients) met the inclusion criteria. Combining the 3 randomized clinical trials involving patients with baseline hemoglobin levels <11 g/dL, change in hemoglobin level was greater for ascorbic acid use compared with standard care (WMD, 0.9 g/dL; 95% CI, 0.5-1.2 g/dL). Compared with standard care, ascorbic acid use also was associated with a statistically significant decrease in rHuEPO dose (WMD, −17.1 U/kg/wk; 95% CI, −26.0 to −8.2 U/kg/wk) and improvement in transferrin saturation (WMD, 7.9%; 95% CI, 5.2-10.5%), with no change in ferritin concentration. Adverse events had questionable relevance to ascorbic acid use; no study reported oxalate levels or occurrence of oxalosis.

Limitations

Small number of studies, heterogeneity between study populations, and study durations were short. Adverse events were poorly reported.

Conclusions

Although the studies are limited by small numbers of subjects, short durations of follow-up, and variable quality, these results suggest that compared with standard care, ascorbic acid use may result in an increase in hemoglobin concentration and transferrin saturation and decrease in rHuEPO requirements. Longer term studies are required to confirm these results, provide information about adverse events, and determine whether these changes translate into improved patient outcomes and cost-effectiveness.

Index Words: Anemia, ascorbic acid, hemodialysis

 

Anemia is common in patients with end-stage renal disease and is an independent risk factor for hospitalization and mortality.1, 2 Although use of recombinant human erythropoietin (rHuEPO) has decreased the need for blood transfusions and improved left ventricular hypertrophy, quality of life, and nutrition,3, 4, 5, 6 an estimated 35% of prevalent patients have persistent anemia (hemoglobin <11 g/dL).7

The cause of this persistent anemia may be related to relative resistance to erythropoietin because of functional iron deficiency, a condition characterized by low transferrin saturation despite normal or increased total-body iron stores (ferritin > 100 and > 500 μg/L, respectively). In these patients, the demand for iron caused by rHuEPO-stimulated erythropoiesis exceeds circulating iron availability, which is limited in turn by the body's ability to release iron from its stores despite normal or increased ferritin levels.8 This results in a state of erythropoietin hyporesponsiveness, defined as failure to achieve a hemoglobin concentration target of 11 g/dL despite use of an rHuEPO dose equivalent to at least 500 U/kg/wk.9

Use of ascorbic acid may enhance iron availability through 2 mechanisms: as a reducing agent that can mobilize iron from its storage sites10 and through its role of integration of iron into the heme moiety.11 Observational studies report an improvement in hemoglobin levels with ascorbic acid use.12, 13, 14, 15 Small randomized trials also suggest a potential benefit of ascorbic acid; however, the effectiveness of this agent is unclear because of variability in results, particularly with different routes of administration. Safety concerns related to potential secondary oxalosis16 also exist and are particularly relevant to patients receiving hemodialysis, who commonly have increased serum oxalate levels.17, 18

Given the potential adverse outcomes associated with refractory anemia in patients with end-stage renal disease, the concern about the safety of the very high doses of rHuEPO required in patients with refractory anemia, and uncertainties pertaining to the role of ascorbic acid in these patients, the objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of ascorbic acid in addition to standard anemia management in patients receiving hemodialysis. Specific outcomes of interest were the effect on hemoglobin level, rHuEPO dose, ferritin concentration, transferrin saturation, and adverse events.

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Methods 

Search Strategy 

We performed this systematic review using a predetermined protocol and in accordance with the quality of reporting of meta-analysis (QUOROM) statement.19 We searched MEDLINE (1966-October 2008), EMBASE (1980-October 2008), and CENTRAL (Cochrane Central Register of Controlled Trials 2008) using the OVID search engine and PubMed (1996-October 2008). Searches were not restricted by language. Three comprehensive search themes were developed using medical subject headings, key words, or database-specific thesaurus terms and combined using the Boolean operator “and.” The first theme was “ascorbic acid”; the second, “anemia”; and the third, “hemodialysis.” Exact search strategies are available online (Item S1). This electronic search was supplemented by reviewing the reference lists of identified citations and the conference proceedings of the American Society of Nephrology (2002-2007).

Study Selection 

Two reviewers (P.P. and V.D.) independently evaluated articles for eligibility in a 2-stage procedure. In the first stage, all identified abstracts were reviewed for possible eligibility. For abstracts selected by either individual in the first stage, the full-text article was retrieved and reviewed by both reviewers in the second stage. Articles then were either selected or excluded on the basis of predefined inclusion criteria, with disagreement resolved by consensus. When only a published abstract was available, the study was included only if all necessary information was available from the authors. Inclusion criteria were: (1) original data, (2) study design (randomized controlled trial), (3) study population (hemodialysis patients), (4) intervention (ascorbic acid), and (5) outcome (change in hemoglobin/hematocrit values or change in rHuEPO dose). Crossover trials also were included provided initial treatment allocation was randomized.

Data Abstraction and Quality Assessment 

Reviewers independently extracted data from all included studies. Study data extracted included study design; baseline demographic, clinical, and laboratory characteristics; and treatment protocol. Outcome data extracted included changes in hemoglobin/hematocrit values, rHuEPO dose, transferrin saturation, and ferritin level and adverse events, when reported. When data were not reported or were unclear, we attempted to contact authors for additional information. Both reviewers independently assessed components of study quality, including study design, randomization process, allocation concealment, blinding, intention-to-treat analysis, and description of loss to follow-up.

Study Outcomes 

The primary outcome was change in mean hemoglobin concentration (grams per deciliter) from study baseline to end of follow-up. Secondary outcomes were change in mean rHuEPO dose (units per kilogram per week), change in mean ferritin concentration (micrograms per liter), change in transferrin saturation (percentage), and adverse events, including secondary oxalosis. Hematocrit values were converted to hemoglobin concentration in grams per deciliter by multiplying by 0.35.20 When rHuEPO doses were reported in units per week, we used a mean weight of 70 kg to standardize values to units per kilogram per week. Studies that used a fixed dose of rHuEPO throughout the trial were not included in the analysis of change in rHuEPO dose.

Statistical Analyses 

Changes in mean hemoglobin concentration, rHuEPO dose, ferritin concentration, and transferrin saturation from baseline to end of follow-up were used to compare groups. When not directly reported, SDs for mean changes were calculated from P values from statistical tests or by imputation based on correlation coefficients estimated from other included studies.21 To ensure results were robust to these assumptions, we performed additional analyses using imputed SDs derived with correlation coefficients of 0, 0.35, and 0.7.22, 23 Results were consistent across this range of correlation coefficients in all analyses, suggesting that these imputations were reasonable.

Weighted mean difference (WMD) was used to pool change-from-baseline comparisons for all outcomes. Random-effects models of DerSimonian and Laird were used to estimate pooled effects. The presence of heterogeneity across trials was reported using the I2 statistic, which quantifies the percentage of variability that can be attributed to between-study differences. Because significant heterogeneity in hemoglobin level change could be expected based on the degree of anemia at study baseline, the WMD for change in hemoglobin level was assessed for only studies with mean baseline hemoglobin levels <11 g/dL. The WMD for changes in rHuEPO dose, ferritin level, and transferrin saturation included all studies. All analyses pooled results from randomized parallel-group studies and from the initial treatment period only from crossover studies24 in which treatment sequence was randomly assigned. Publication bias was assessed using Begg's and Egger's tests; however, we draw attention to the limited power of these tests to detect publication bias when the number of included studies is small.25 Statistical analyses were performed using Stata, version 10.0 (Stata Corp, College Station, TX).

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Results 

Identification of Studies 

Figure 1 shows progress through the stages of the systematic review. Of 157 potentially relevant citations screened, 134 were excluded and 23 publications were retrieved for further review. After this review, 17 studies were excluded, leaving 6 randomized controlled trials that met inclusion criteria for the systematic review (4 parallel-group26, 27, 28, 29 and 2 crossover randomized controlled trials30, 31). Chance-corrected agreement between the 2 independent reviewers who evaluated study eligibility was excellent (κ = 1.0).

Study Characteristics 

A total of 326 patients were included from the 6 randomized controlled trials (Table 1). All studies were designed to test the effect of ascorbic acid on erythropoiesis in hemodialysis patients. Mean age of study participants ranged from 41.1-60.0 years, with a study duration of 2-6 months. Three trials29, 30, 31 (n = 125) included participants with baseline mean hemoglobin levels <11 g/dL (range, 9.1-10.3 g/dL), whereas 3 trials26, 27, 28 (n = 201) included individuals with baseline mean hemoglobin levels ≥ 11 g/dL (range, 11.0-12.6 g/dL). Ascorbic acid doses ranged from 500 mg intravenously once weekly to 500 mg intravenously 3 times weekly (all administered after hemodialysis). Five studies administered ascorbic acid intravenously,26, 27, 29, 30, 31 whereas 1 study administered it orally.28 One study26 used a run-in phase (phase 1), and only participants responding to ascorbic acid treatment were randomly assigned and included in phase 2. Only data from phase 2 were included in this analysis. All studies used concomitant erythropoietin therapy with baseline doses ranging from 47-477 U/kg/wk. Erythropoietin dose was adjusted by investigators during the study in all trials except that of Giancaspro et al,30 in which the dose was held constant. Intravenous iron was given in all studies in either constant or adjusted doses except for the study by Sezer et al.26 Baseline values for transferrin saturation (range, 17.5%-43.8%) and ferritin (range, 259-1,300 μg/L) were variable across studies, and only 1 trial30 involved a population that met the usual definition of functional iron deficiency (transferrin saturation < 20% and ferritin >100 μg/L).

Table 1. Characteristics of Included Studies
ReferenceStudy DesignDuration (mo)Mean Age (y)Hb or Hct TargetAscorbic Acid InterventionrHuEPO ProtocolIron ProtocolNo. of Participants
AscorbicAcidControl
Giancaspro et al,30 2000Crossover359.912 g/dL500 mg IV 3×/wkDose constant; if monthly Hb >12 g/dL, ↓ rHuEPO dose by halfIV iron only given for monthly ferritin <100 μg/L1212
Sezer et al,26 2002Parallel241.930%-36%500 mg IV 1×/wkAdjusted every 2 wk to maintain target; if Hct >36%, ↓ rHuEPO by 2,000 U/wkNone given1515
Deira et al,27 2003Parallel660.0None200 mg IV 3×/wkDose constant during first 3 mo, adjusted during second 3 mo3 patients (1 ascorbic acid, 2 controls) given ferric gluconate, 62.5 mg/wk, throughout study99
Keven et al,31 2003Crossover641.111-12 g/dL500 mg IV 3×/wkAdjusted every mo to maintain targetFor ferritin 200-500 μg/L and TSAT 30-40%, ferric sucrose, 100 mg IV, 2×/mo given3030
Chan et al,28 2005Parallel3NR12 g/dL500 mg orally 3×/wkAdjusted every mo to maintain targetIV iron given to achieve ferritin >500 μg/L7083
Attallah et al,29 2006Parallel649.811.5-12.5 g/dL300 mg IV 3×/wkAdjusted every mo to maintain targetFerric gluconate given to achieve monthly ferritin >600 μg/L and TSAT >25%2021

Note: Conversion factor for Hb in g/dL to g/L, ×10. No conversion necessary for ferritin in μg/L and ng/mL.

Abbreviations: Hb, hemoglobin; Hct, hematocrit; IV, intravenous; NR, not reported; rHuEPO, recombinant human erythropoietin; TSAT, transferrin saturation.

Study Quality 

Criteria used to assess study quality are listed in Table 2. In general, study quality was poor and only 1 trial was blinded. In the crossover studies,30, 31 there were no washout periods and analysis of results suggested that carryover effects were present; thus, these studies were analyzed as parallel-group studies, including data from only the first period of the trial.24

Table 2. Quality Assessment of Included Studies
ReferenceDesignRandomization Process DescribedAllocation ConcealmentBlindingIntention-to-Treat AnalysisDescription of Loss to Follow-upLost to Follow-up (%)
Giancaspro et al,30 2000CrossoverYesNRNRYesYes11
Sezer et al,26 2002ParallelNoNRNRYesYes0
Deira et al,27 2003ParallelNoNRNRYesYes10
Keven et al,31 2003CrossoverNoNRYesYesYes5
Chan et al,28 2005ParallelNoNRNoYesNo28
Attallah et al,29 2006ParallelYesYesNRYesYes2

Abbreviation: NR, not reported.

Data Synthesis and Analysis 

Effect of Ascorbic Acid on Hemoglobin Concentration 

Three trials29, 30, 31 (n = 125) included patients with baseline hemoglobin levels <11 g/dL and reported changes in hemoglobin concentrations. In these studies, mean changes in hemoglobin concentration range were 0.8-1.8 g/dL in the ascorbic acid groups and −0.1 to 1.1 g/dL in the control groups. In a random-effects model, change in the WMD for hemoglobin concentration was statistically significant, with ascorbic acid use resulting in a 0.9 g/dL increase in hemoglobin level compared with controls (WMD, 0.9 g/dL; 95% confidence interval [CI], 0.5-1.2 g/dL; I2 = 0.0%; Fig 2).

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  • Figure 2. 

    Forest plot of studies comparing the effect of ascorbic acid versus control on change in hemoglobin concentration (grams per deciliter). Abbreviation: CI, confidence interval.

Effect of Ascorbic Acid on rHuEPO Dose 

The effect of ascorbic acid use on the ability to decrease the rHuEPO dose was assessed in 5 trials26, 27, 28, 29;31 (n = 303). In these studies, mean change in rHuEPO dose ranged from −48 to 1 U/kg/wk in the ascorbic acid groups and −27 to 10 U/kg/wk in the control groups. Using a random-effects model, use of ascorbic acid was associated with a significant decrease in rHuEPO dose compared with controls (WMD, −17.1 U/kg/wk; 95% CI, −26.0 to −8.2 U/kg/wk; I2 = 1.6%; Fig 3). When the study with the highest starting doses of rHuEPO29 was excluded, ascorbic acid use was still associated with a significant decrease in rHuEPO dose (WMD, −13.7 U/kg/wk; 95% CI, −26.6 to −0.8 U/kg/wk; I2= 12.4%). When analysis was stratified by degree of anemia at baseline, decreases in rHuEPO dose were more pronounced in studies in which baseline hemoglobin levels were <11 g/dL29, 31 (WMD, −23.4 U/kg/wk; 95% CI, −34.4 to −12.3 U/kg/wk; I2 = 0.0%). When analysis was stratified further by duration of study, decreases in rHuEPO dose were greater in studies > 3 months27, 29, 31 (WMD, −22.2 U/kg/wk; 95% CI, −32.5 to −11.8 U/kg/wk; I2 = 0.0%).

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  • Figure 3. 

    Forest plot of studies comparing the effect of ascorbic acid versus control on change in recombinant human erythropoietin dose (units per kilogram per week). Abbreviation: CI, confidence interval.

Effect of Ascorbic Acid on Iron Indices 

The effect of ascorbic acid use on ferritin concentration (5 trials26, 27, 28, 29, 30 [n = 266]) was variable, with mean changes in ferritin level ranges of −403 to −21 μg/L in the ascorbic acid groups and −397 to 49 μg/L in the control groups. Pooled results using a random-effects model showed a small nonsignificant decrease in ferritin concentration in ascorbic acid users over controls, although this result did not achieve statistical significance (WMD, −34 μg/L; 95% CI, −106 to 37 μg/L; I2 = 0.0%; Fig 4).

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  • Figure 4. 

    Forest plot of studies comparing the effect of ascorbic acid versus control on change in ferritin concentration (micrograms per liter). Abbreviation: CI, confidence interval.

Five trials26, 27, 29, 30, 31 (n = 173) measured change in transferrin saturation, with mean change in transferrin saturation ranging from 6.5% to 10.3% in the ascorbic acid groups and −11.8% to 9.3% in the control groups. Pooled results for these 5 studies using a random-effects model showed a statistically significant increase in transferrin saturation for ascorbic acid compared with controls (WMD, 7.9%; 95% CI, 5.2 to 10.5%; I2 = 0.0%; Fig 5).

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  • Figure 5. 

    Forest plot of studies comparing the effect of ascorbic acid versus control on change in transferrin saturation (percentage). Abbreviation: CI, confidence interval.

Publication Bias 

We tested for publication bias for studies based on the primary outcome, with no evidence of small-sample effects using Egger's (P = 0.5) or Begg's test (P = 0.6).29, 30, 31

Adverse Events 

Reporting of adverse events was poor, and those reported had questionable relevance to the use of ascorbic acid. Reported events in the ascorbic-acid group included 1 episode of cellulitis, 2 infected accesses, 3 myocardial infarctions, and 1 deep venous thrombosis.29 One study27 reported a patient who developed miliary tuberculosis, and in another study,31 1 patient developed a gastrointestinal bleed while receiving ascorbic acid. Adverse events were not reported in 2 studies.26, 28 No study reported changes in serum oxalate levels or the clinical occurrence of oxalosis.

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Discussion 

In this meta-analysis, we found in anemic patients receiving hemodialysis that short-term use of ascorbic acid showed a small improvement in hemoglobin concentration compared with standard care. We also found that ascorbic acid decreased rHuEPO requirements and increased transferrin saturation compared with standard care. Although poorly reported, adverse events did not appear to be increased in patients receiving short-term ascorbic acid therapy.

Although administering iron to patients with functional iron deficiency on rHuEPO therapy has been beneficial in increasing hemoglobin levels,32, 33 administering iron to patients who are already iron overloaded may increase the risk of hemosiderosis34 and bacterial infection.35 Given the potential adverse outcomes associated with the use of high erythropoietin doses,36 in theory, it may be important to decrease erythropoietin requirements.

Ascorbic acid also has been shown to stabilize degradation of the soluble intracellular ferritin fraction to the insoluble hemosiderin fraction, resulting in an increase in the cytosolic pool of iron stores in the reticuloendothelial system.10 This increased labile iron pool is available for release to transferrin, which then transports it to the erythroid marrow, where it is used in erythropoiesis.37 In the marrow, ascorbic acid also maintains iron in the reduced (ferrous) state, which is the form required for incorporation into protoporphyrin for heme synthesis.11 Our findings are consistent with these mechanisms in hemodialysis patients, in whom we observed a significant increase in transferrin saturation with ascorbic acid treatment.

Despite concerns about secondary oxalosis, adverse-event reporting from studies included in this systematic review did not comment on this outcome. Caution is warranted because other studies have shown that plasma oxalate levels increase significantly within a 1-2-month period of ascorbic acid use at doses that were one-third those used in some studies included in this meta-analysis.38, 39 Although doses of ascorbic acid produce significant increases in plasma oxalate levels in dialysis patients,40 there may not be a direct correlation between plasma ascorbate and oxalate levels.41

There are limitations to this systematic review. First, baseline characteristics of patients varied with respect to hemoglobin concentration, rHuEPO dose, ferritin level, and transferrin saturation. However, analyses that stratified by these factors resulted in effects consistent with those reported here. Second, there is evidence that serum ascorbate levels are variable, depending on the route of administration42; however, sensitivity analyses eliminating the study using oral ascorbic acid28 did not change our results. Third, most studies included a modest number of subjects with short duration of treatment, thus limiting generalizability of findings to that of short-term use. Fourth, adverse-event reporting was limited across studies, possibly because of the low event rate in these trials. Finally, as in other meta-analyses, we were limited by the data reported within the original studies.

Despite these limitations, this meta-analysis suggests potential short-term efficacy of ascorbic acid in improving hemoglobin concentrations and transferrin saturations and decreasing rHuEPO doses in hemodialysis patients. Given that results of meta-analyses are restricted by the quality of the included studies, larger and longer trials of better method quality extending beyond surrogate markers and including hard clinical end points are required to confirm these results and provide better information about important adverse events.

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Acknowledgements 

Support: Drs Deved, James, and Walsh are supported by an Alberta Heritage Foundation for Medical Research Award. Drs James and Walsh also are supported by a Kidney Research Scientist Education and Training (KRESCENT) Joint Fellowship. Drs Tonelli and Hemmelgarn are supported by Population Health Investigator Awards from the Alberta Heritage Foundation for Medical Research. Drs Tonelli, Manns, and Hemmelgarn are supported by New Investigator Awards from the Canadian Institutes for Health Research.

Financial Disclosure: None.

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Supplementary Material 

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Supplementary Item S1.

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 Originally published online as doi:10.1053/j.ajkd.2009.06.040 on September 24, 2009.

PII: S0272-6386(09)00988-3

doi:10.1053/j.ajkd.2009.06.040

American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1089-1097, December 2009

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