Randomized, crossover study of the effect of vitamin C on EPO response in hemodialysis patients

Dialysis Therapies

Randomized, Crossover Study of the Effect of Vitamin C on EPO Response in Hemodialysis Patients Kenan Keven, MD, Sim Kutlay, MD, Go¨khan Nergizoglu, MD, and Sehsuvar Ertu¨rk, MD ● Background: Vitamin C has been reported to be an effective adjuvant agent in the treatment of anemia in iron-overloaded hemodialysis patients. We aim to evaluate its effect on erythropoietin (EPO) response in a prospective, randomized, double-blind, crossover study. Methods: Sixty-three patients were randomly divided into two groups. Group 1 was treated with intravenous vitamin C, 500 mg, three times a week, and group 2, with placebo for 6 months. During the second 6-month period, group 1 was treated with placebo, and group 2, with the same dose of vitamin C. Thirty patients in group 1 and 28 patients in group 2 completed the study. Hemoglobin levels, weekly EPO dose, and ratio of EPO to hemoglobin as an index of EPO need were determined at both baseline and the end of the two periods, together with other parameters known to be associated with EPO response. Results: Twenty patients in group 1 (66.7%) and 18 patients in group 2 (64.3%) were responsive to vitamin C. In both groups, vitamin C resulted in a significant increase in hemoglobin levels (P < 0.0001 for both) and a significant decrease in EPO-hemoglobin ratio (P < 0.0001, P ⴝ 0.019). Transferrin saturation also increased with vitamin C treatment in both groups (P ⴝ 0.009, P ⴝ 0.005). All these parameters remained stable with placebo in both groups. Other parameters did not change throughout the study. Conclusion: Vitamin C can be used as an effective adjuvant therapy to EPO in hemodialysis patients. Further studies are needed to determine possible predictors of hematologic response to vitamin C. Am J Kidney Dis 41:1233-1239. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Adjuvant therapy; anemia; end-stage renal disease (ESRD); erythropoietin (EPO); hemodialysis (HD); vitamin C.

T

HE MAIN CAUSE of anemia of end-stage renal failure is insufficient synthesis and secretion of erythropoietin (EPO).1 Recombinant human EPO has been effective in the treatment of anemia in these patients,2,3 although there is wide variability in doses of EPO.4 Iron deficiency, inflammation, malnutrition, hyperparathyroidism, aluminum intoxication, and deficiency of several vitamins are the major contributing factors for the development of anemia and insufficient response to EPO in hemodialysis patients.5-8 Several studies have searched for adjuvant therapies to EPO to provide better hemoglobin levels and lower doses of EPO to make this treatment more cost-effective.9-13 Iron replacement is one of the most efficient adjuvant therapies to EPO. Recently, intravenous iron replacement has received increasing attention in most hemodialysis units to prevent iron deficiency and promote better anemia control.14 Evaluation of iron status is very important because some patients may have functional iron deficiency, in which iron mobilization and utilization are defective despite enough stored iron in tissues. In these patients, transferrin saturation levels usually are low (⬍20%) and there is an insufficient response to increased doses of EPO, whereas

intravenous iron can induce a better response.15 However, it can be a potential hazard leading to iron overload, in which serum ferritin level is greater than 800 ng/mL (1,798 pmol/L). It was reported that chronic hemodialysis patients had lower vitamin C levels than healthy subjects,16 possibly caused by the loss of vitamin C in each hemodialysis session, increased oxidative stress causing increased consumption, or insufficient dietary intake.17,18 It is noteworthy that vitamin C seems to be involved in iron release from deposited tissues and increases iron availability for heme synthesis.19-21 Intravenous vitamin C has been shown to have an additive From the Department of Nephrology, Ankara University Medical School, Ankara, Turkey. Received November 2, 2002; accepted in revised form January 10, 2003. Supported in part by grant no. 20010809049 from Ankara University Research Fund. Presented in part at the American Society of Nephrology/ International Society of Nephrology World Congress of Nephrology, October 13-17, 2001, San Francisco, CA. Address reprint requests to Sehsuvar Ertu¨rk, MD, Ankara University Medical School, Ibni Sina Hospital, 06100, Ankara, Turkey. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4106-0013$30.00/0 doi:10.1016/S0272-6386(03)00356-1

American Journal of Kidney Diseases, Vol 41, No 6 (June), 2003: pp 1233-1239

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effect on EPO in hemodialysis patients, especially those with iron overload and functional iron deficiency.22-26 In these studies, intravenous vitamin C treatment resulted in better anemia control. However, there is no controlled study evaluating the effect of regular intravenous vitamin C on EPO response in patients with normal iron status. Therefore, we conducted a prospective, placebo-controlled, double-blind, crossover study to determine whether regular intravenous vitamin C replacement may induce a better EPO response in hemodialysis patients. METHODS The study was approved by the Ethical Committee of Ankara University Medical School (Ankara, Turkey), and all patients gave an informed consent before participation. Seventy-one patients on maintenance hemodialysis therapy in our hemodialysis unit were evaluated. Inclusion criteria were age older than 18 years, a minimum of 6 months of hemodialysis treatment, stable hemoglobin level for at least 3 months on a stable dose of EPO, and unchanged maintenance intravenous iron therapy. Exclusion criteria were absolute iron deficiency (transferrin saturation ⬍ 20%, serum ferritin level ⬍100 ng/mL [⬍224.7 pmol/L]), vitamin B12 deficiency, folate deficiency, any blood transfusion during the study, bleeding, hemoglobinopathy, hemolysis, aluminum toxicity, development of malignancy, acute infectious and inflammatory processes, advanced liver disease, change in iron replacement therapy, and taking multivitamin preparations. Eight patients were excluded before enrollment, 32 patients were randomly assigned to group 1, and 31 patients, to group 2. Reasons for exclusions were absolute iron deficiency in 7 patients and pulmonary tuberculosis in 1 patient. An additional 2 patients in group 1 were excluded during the first 6-month period because of gastrointestinal bleeding and transition to continuous ambulatory peritoneal dialysis treatment in 1 patient each. In group 2, one patient reporting pruritus was excluded during the first period, and 2 patients who underwent kidney transplantation were excluded during the second period. After excluding these patients, 60 patients (30 patients in each group) completed the first period, and 58 patients (30 patients, group 1; 28 patients, group 2) completed the second period. Causes of end-stage renal failure were chronic tubulointerstitial nephritis in 21 patients, chronic glomerulonephritis in 15 patients, diabetes mellitus in 7 patients, hypertensive nephrosclerosis in 5 patients, and unknown in 12 patients. During the first 6-month period, 500 mg of vitamin C (Redoxon IV; Roche, Geneva, Switzerland) was administrated intravenously to patients in group 1 at the end of each hemodialysis session, and placebo was administered to patients in group 2 by a dialysis nurse. During the second 6-month period, group 1 was administered placebo, whereas group 2 was administrated vitamin C of the same dose and frequency. Neither the treating physician nor patients knew the identity of the administered agent. Hematologic response

to vitamin C is defined as an increase in hemoglobin level greater than 1 g/dL (10 g/L) on a stable EPO dose or a decrease in EPO dose greater than 30% with a stable hemoglobin level. Patients were dialyzed for 4 hours thrice weekly using a semisynthetic or synthetic hollow-fiber membrane (Clirans E series; Terumo Europe NV, Leuven, Belgium; or Hemoflow F; Fresenius Polysulfone, Hamburg, Germany) and bicarbonate dialysate bath. EPO was administered subcutaneously after each hemodialysis session, and EPO dose was determined every month throughout the study according to National Kidney Foundation-Dialysis Outcomes Quality Initiative guidelines27 by a nephrologist (G.N.), who was blinded to whether vitamin C or placebo was being administered. Target hemoglobin levels were 11 to 12 g/dL (110 to 120 g/L). Maintenance iron replacement of 100 mg of intravenous iron (Ferric sucrose IV; Vifor Int, St Gallen, Switzerland) was administrated twice a month to all patients with normal iron status (ie, serum ferritin, 200 to 500 ng/mL [449.4 to 1,123.5 pmol/L] and transferrin saturation, 30% to 40%). However, to avoid iron overload (ie, serum ferritin ⱖ 800 ng/mL [1,798 pmol/L] and/or transferrin saturation ⱖ 50%), maintenance intravenous iron therapy was withheld and resumed at a dose reduced by one half when serum ferritin levels declined to less than 800 ng/mL (1,798 pmol/ L).28 Eight of 30 patients in group 1 and 6 of 28 patients in group 2 had iron overload before the institution of vitamin C treatment. No patient was found to have absolute iron deficiency.

Laboratory Measurements Fasting blood samples were drawn before the hemodialysis session. Hemoglobin levels were measured every month, and serum biochemistry was studied every 3 months. Serum iron, total iron binding capacity (TIBC), serum ferritin, vitamin B12, and folate levels were measured at baseline and every 6 months throughout the study. Serum iron was measured by means of a colorimetric method, and TIBC was evaluated by TIBC Microtest (ThermoDMA, Arlington, TX). Transferrin saturation was calculated using the formula: serum iron ⫻ 100/TIBC. C-Reactive protein (CRP) was measured at baseline and 6-month intervals using a nephelometric method (Dade Behring). Adequacy of dialysis (Kt/ Vurea) was evaluated using the Depner formula.29 Intact parathyroid hormone (PTH) was measured by means of radioimmunoassay using a commercial kit (Gamma-BCT Intact PTH immunoradiometric assay; IDS, Boldon, UK) every 6 months. Serum aluminum level was determined using the method previously described.30

Statistical Analyses Data were analyzed first for normality of distribution using the Kolmogorov-Smirnov test. Normally distributed data are presented as mean ⫾ SD, and non–normally distributed data, as median value and range. Differences between groups were analyzed by means of Student’s t-test, MannWhitney U, or chi-square test, as appropriate. P less than 0.05 is considered statistically significant.

VITAMIN C AND EPO RESPONSE IN HEMODIALYSIS Table 1.

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Patient Demographic Features and Relevant Laboratory Data

Sex (men/women) Age (y) Dialysis duration (mo) Kt/Vurea Hemoglobin (g/dL) EPO dose (IU/wk) EPO-hemoglobin ratio Transferrin saturation (%) Ferritin (ng/mL) Albumin (g/dL) CRP (mg/L) Vitamin B12 (pg/mL) Folate (ng/mL) PTH (pg/mL) Aluminum (␮g/L)

Group 1 (n ⫽ 30)

Group 2 (n ⫽ 30)

14/16 40.2 ⫾ 9.5 52 ⫾ 46 3.66 ⫾ 0.73 9.7 ⫾ 1.2 8,567 ⫾ 3,114 906 ⫾ 370 28.2 ⫾ 10.0 382 (105–1,372) 4.0 ⫾ 0.5 3.1 (3.1–77.3) 464 ⫾ 219 9.7 ⫾ 4.2 197 (9-1,919) 14.8 ⫾ 8.7

13/17 42.0 ⫾ 14.3 46 ⫾ 47 3.80 ⫾ 0.91 10.3 ⫾ 1.4 6,967 ⫾ 3,178 700 ⫾ 342 30.1 ⫾ 14.0 259 (100–2,536) 3.9 ⫾ 0.6 3.1 (3.1–84.0) 480 ⫾ 214 9.5 ⫾ 5.2 108 (12-2,171) 13.2 ⫾ 8.9

NOTE. Values expressed as mean ⫾ SD or median (range). SI conversion factors for variables are as follows: hemoglobin, ⫻ 10 g/L; ferritin, ⫻ 2.247 pmol/L; albumin, ⫻ 10 g/L; vitamin B12, ⫻ 0.738 pmol/L; folate, ⫻ 2.266 nmol/L; PTH, ⫻ 1 ng/L; aluminum, ⫻ 0.0371 ␮mol/L.

RESULTS

Patients in both groups were similar with regard to age, sex, causes of end-stage renal failure, duration of hemodialysis therapy, Kt/ Vurea, transferrin saturation, ferritin, albumin, CRP, PTH, vitamin B12, folate, and serum aluminum (P ⬎ 0.05) values. There was no significant difference in total dose of intravenous iron between the groups. Although baseline hemoglobin level tended to be lower and both EPO dose and EPO-hemoglobin ratio tended to be greater in group 1 than group 2, differences in these parameters did not reach statistical significance (Table 1).

In both groups, vitamin C treatment resulted in significant increases in hemoglobin levels and significant decreases in ratios of EPO to hemoglobin, as an index of EPO need (Fig 1). Twenty patients in group 1 (66.7%) and 18 patients in group 2 (64.3%) were responsive to vitamin C. In responder patients, hemoglobin levels increased from 9.6 ⫾ 1.1 to 11.9 ⫾ 1.3 g/dL (96 ⫾ 11 to 119 ⫾ 13 g/dL) in group 1 and from 10.8 ⫾ 1.8 to 12.6 ⫾ 1.2 g/dL (108 ⫾ 18 to 126 ⫾ 12 g/L) in group 2. Mean reductions in EPO doses in responder patients were 2,650 ⫾ 2,368 IU/wk in group 1 and 2,333 ⫾ 4,144 IU/wk in group 2. There were no statistically significant differences

Fig 1. (Left) Hemoglobin levels and (right) ratios of EPO dose to hemoglobin before (open circles) and after (solid squares) vitamin C treatment in both groups. Bars represent 95% CIs for mean. *P < 0.0001 versus pretreatment value. #P ⴝ 0.019 versus pretreatment value. To convert hemoglobin in g/dL to g/L, multiply by 10.

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KEVEN ET AL Table 2.

Comparison of Changes in Hemoglobin Levels and EPO Doses Between Patients With Normal Iron Status and Iron Overload Group 1

Hemoglobin (g/dL)

EPO dose (IU/wk)

Group 2

Months

Normal Iron Status

Iron Overload

P

Normal Iron Status

Iron Overload

P

0–6 6–12 0–12 0–6 6–12 0–12

1.8 ⫾ 1.7 ⫺0.3 ⫾ 1.7 1.5 ⫾ 1.5 ⫺1,363 ⫾ 3,110 591 ⫾ 2,702 ⫺772 ⫾ 3,465

1.6 ⫾ 1.6 ⫺0.1 ⫾ 1.7 1.5 ⫾ 2.3 ⫺1,375 ⫾ 2,387 625 ⫾ 2,387 ⫺750 ⫾ 1,832

NS NS NS NS NS NS

1.1 ⫾ 2.3 0.7 ⫾ 1.6 1.7 ⫾ 2.0 708 ⫾ 3,099 ⫺682 ⫾ 4,051 227 ⫾ 4,587

1.4 ⫾ 1.5 0.9 ⫾ 1.3 2.2 ⫾ 1.2 667 ⫾ 3,266 ⫺2,167 ⫾ 3,250 ⫺1,500 ⫾ 3,450

NS NS NS NS NS NS

NOTE. To convert hemoglobin from g/dL to g/L, multiply by 10. Abbreviation: NS; not significant.

in any study parameters between responders and nonresponders. Although baseline CRP levels tended to be lower in responders than nonresponders in group 1 (P ⫽ 0.053), such a difference was not observed in group 2. There was no significant difference in percentage of patients having a response to vitamin C in those of normal iron status and iron overload, although the response rate tended to be greater in patients with iron overload (63.6% versus 75%, group 1; 59.1% versus 83.3%, group 2, respectively; P ⬎ 0.05 for both). Similarly, changes in hemoglobin levels, EPO doses, and EPO-hemoglobin ratios were the same in patients with normal iron status and iron overload (Table 2). During the first period, hemoglobin levels increased (P ⬍ 0.0001), whereas both EPO doses and EPO-hemoglobin ratios significantly decreased (P ⫽ 0.015 and P ⬍ 0.0001, respectively) in group 1 on vitamin C treatment (Table 3). Mean reduction in EPO dose was 1,366 ⫾ 2,895 IU/wk in group 1 on vitamin C treatment. Transferrin saturation also increased (P ⫽ 0.009), Table 3.

whereas the other parameters, including Kt/Vurea and levels of albumin, CRP, ferritin, vitamin B12, and folate, did not change. In group 2, although hemoglobin level, EPO dose, and EPO-hemoglobin ratio slightly increased on placebo therapy, differences in these parameters did not reach a statistically significant level (P ⬎ 0.05). Also, no differences in transferrin saturation and ferritin levels were noticed. Similarly, no significant differences were found in Kt/Vurea and levels of albumin, CRP, PTH, vitamin B12, or folate at the end of the first 6 months in group 2. In the second period of the study, there were no significant changes in hemoglobin level, EPOhemoglobin ratio, transferrin saturation, or ferritin level in group 1 on placebo treatment. Similarly, no significant differences were found in Kt/Vurea, serum albumin, PTH, vitamin B12, or folate levels. Although not significant, there was an increase of 643 ⫾ 2,670 IU/wk in EPO dose (P ⬎ 0.05). In group 2, both hemoglobin level (P ⬍

Effect of Vitamin C on Hematologic Parameters in Both Groups Group 1 Before

Hemoglobin (g/dL) EPO dose (IU/wk) EPO-hemoglobin ratio Transferrin saturation (%) Ferritin (ng/mL)

9.7 ⫾ 1.2 8,567 ⫾ 3,114 906 ⫾ 370 28.2 ⫾ 10.0 382 (105-1,372)

After

Group 2 P

11.4 ⫾ 1.6 ⬍0.0001 7,200 ⫾ 3,994 0.015 653 ⫾ 389 ⬍0.0001 38.5 ⫾ 19.3 0.009 381 (105-1,166) NS

Before

After

P

11.0 ⫾ 1.6 7,667 ⫾ 3,356 749 ⫾ 445 31.9 ⫾ 11.5 263 (105-1,998)

12.2 ⫾ 1.4 6,679 ⫾ 4,074 582 ⫾ 400 43.3 ⫾ 14.9 391 (100-2,412)

⬍0.0001 NS 0.019 0.005 NS

NOTE. Values expressed as mean ⫾ SD or median (range). SI conversion factors for variables are as follows: hemoglobin, ⫻10 g/L; ferritin, ⫻2.247 pmol/L. Abbreviation: NS, not significant.

VITAMIN C AND EPO RESPONSE IN HEMODIALYSIS Table 4.

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Comparison of Changes in Hemoglobin Levels, EPO Doses, and EPO-Hemoglobin Ratios Between Groups

Change in hemoglobin (g/dL)

Change in EPO dose (IU/wk)

Change in EPO-hemoglobin ratio

Months

Group 1

Group 2

P

0–6 6–12 0–12 0–6 6–12 0–12 0–6 6–12 0–12

1.8 ⫾ 1.6 ⫺0.3 ⫾ 1.6 1.5 ⫾ 1.7 ⫺1,367 ⫾ 2,895 600 ⫾ 2,581 ⫺767 ⫾ 3,019 ⫺253 ⫾ 329 61 ⫾ 277 ⫺191 ⫾ 346

1.1 ⫾ 2.1 0.7 ⫾ 1.5 1.9 ⫾ 1.8 700 ⫾ 3,075 ⫺1,000 ⫾ 3,887 ⫺142 ⫾ 4,369 22 ⫾ 401 ⫺140 ⫾ 320 ⫺104 ⫾ 441

NS 0.021 NS 0.01 NS NS 0.005 0.013 NS

NOTE. To convert hemoglobin from g/dL to g/L, multiply by 10. Abbreviation: NS, not significant.

0.0001) and transferrin saturation (P ⫽ 0.005) increased and EPO-hemoglobin ratio significantly decreased (P ⫽ 0.019) on vitamin C treatment. The mean decrease of 1,000 ⫾ 3,887 IU/wk in EPO dose did not reach a significant level (Table 3). There were no significant differences in Kt/Vurea and levels of albumin, CRP, ferritin, PTH, vitamin B12, and folate in group 2 on vitamin C treatment. We also compared changes in hemoglobin levels, EPO doses, and EPO-hemoglobin ratios between the two groups and looked at the sequence effects (Table 4). At the end of the first period, changes in hemoglobin levels from baseline were the same, whereas EPO dose changes were significantly different between the groups (P ⫽ 0.01). At the end of the second period, changes in hemoglobin levels from the beginning were significantly different between the groups (P ⫽ 0.021), whereas the difference in EPO dose changes did not reach a statistically significant level (P ⫽ 0.068). During both periods, changes in EPO-hemoglobin ratios were significantly different between the two groups (P ⫽ 0.005 and P ⫽ 0.013, respectively). When changes were evaluated between baseline parameters and those of the end of the study (ie, from zero to end of month 12), there were no significant differences between the two groups (Table 4). DISCUSSION

In this prospective, randomized, double-blind, crossover study, we show that intravenous vitamin C can be used as an effective adjuvant

therapy to EPO in hemodialysis patients. Approximately 65% of patients responded to vitamin C treatment with almost a 2-g/dL (20-g/L) increase in hemoglobin level, together with a 2,500IU/wk (30%) reduction in EPO dose. In addition, apart from confirmation of recent studies that recommend a beneficial effect of vitamin C in patients with iron overload and functional iron deficiency, we found a better response to EPO in patients with normal iron status, as well. It is reported that vitamin C levels in chronic hemodialysis patients are lower that those in healthy subjects because of loss through the dialyzer, increased consumption, and inadequate dietary intake.17,18 Descombes et al16 reported that 1,000 to 1,500 mg/wk or 150 to 200 mg/d of vitamin C could provide normal vitamin C levels in the majority of hemodialysis patients. The relationship between vitamin C and iron metabolism has been defined in several studies. Bothwell et al31 reported that Bantu people with scurvy had increased iron stores in tissues, and vitamin C seemed to have a role of enhanced iron mobilization from tissues, including reticuloendothelial system to transferrin, that produced increased iron availability.19-21 Also, vitamin C has a role in the enzymatic incorporation of iron into protophorphyrin for heme synthesis.32 Therefore, it seems logical that vitamin C can be used as an adjuvant therapy to EPO in hemodialysis patients with sufficient iron status. However, Gastaldello et al22 showed the beneficial effect of intravenous vitamin C in four iron-overloaded hemodialysis patients, whereas no effect on hematocrit was achieved in seven patients with

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normal iron status. In that study, dose of intravenous vitamin C was defined as 1,000 mg/wk, and study duration was only 3 months. More recently, Giancaspro et al25 studied 27 hemodialysis patients with functional iron deficiency. They reported that patients administrated 500 mg of intravenous vitamin C three times a week for 3 months had significant increases in both hemoglobin and hematocrit levels. They also found that cessation of vitamin C therapy led to deterioration in hemoglobin and hematocrit levels. Tarng and Huang24 also studied the effect of intravenous vitamin C (300 mg postdialysis three times a week for 8 weeks) as an adjuvant therapy for EPO in hemodialysis patients with hyperferritinemia. Fifty-two patients completed the study. Patients were divided into two groups: the intravenous vitamin C treatment group (37 patients) and control group (15 patients). In the vitamin C treatment group, 18 patients were defined as responders to vitamin C, in whom hematocrit levels increased 3% or more or a decrease in EPO dose of more than 25% over baseline value at study completion. Nineteen patients were found to be nonresponders. In responders, there was a 24% reduction in EPO dose after 8 weeks. In that study, transferrin saturation less than 25% and erythrocyte zinc protophorphyrine level greater than 105 ␮mol/ mol heme were found to be predictors for response to intravenous vitamin C. Regarding these studies and a possible effect of vitamin C on iron metabolism, it can be worthwhile that vitamin C can have an additional beneficial effect on EPO response, not only for patients with functional iron deficiency or iron overload, but also for patients with normal iron status. It is well known that the definitions of iron overload and functional iron deficiency depend on iron parameters. Whereas transferrin saturation is usually greater than 50% in iron overload, it is low (usually ⬍20%) in functional iron deficiency. Nevertheless, there are many patients with transferrin saturation greater than 20% who are functionally iron deficient. Therefore, defining a single level of transferrin saturation and ferritin that is optimal for all hemodialysis patients is very difficult. In our study, some patients had hyperferritinemia. However, the number of responder patients, increase in hemoglobin levels, and decrease in both EPO doses

KEVEN ET AL

and EPO-hemoglobin ratios were not different in patients with a ferritin level greater or less than 800 ng/mL (1,798 pmol/L). We acknowledge that the present study has several limitations. First, we could not find a possible mechanism responsible for better anemia control with intravenous vitamin C treatment. In addition, approximately 65% of patients were responders in both groups, and no parameter could be suggested as a predictor of response to vitamin C. However, similar to previous studies, there was a significant increase in transferrin saturation with vitamin C treatment in both groups in the present study. This finding can make the effective mechanism of vitamin C on iron metabolism more favorable. Second, we did not determine levels of plasma ascorbate, the reduced form of vitamin C, in this study. Therefore, we cannot exclude the possibility that the results seen are caused by correction of vitamin C deficiency. Another possible mechanism for the beneficial effect of vitamin C on response to EPO may be the correction in reticuloendothelial blockade of iron that diminishes EPO responsiveness by reducing iron availability. However, this mechanism potentially can be hazardous, especially in patients with occult infection, in whom locking away iron is a wellknown mechanism the body uses to fight off the infection. In such patients, vitamin C may promote electron exchange and enhance iron toxicity to cellular constituents. Therefore, we recommend further studies to clarify both cellular effects and the safety of this treatment in hemodialysis patients. Finally, long-term high doses of vitamin C treatment might be a potential risk for the development of secondary oxalosis in hemodialysis patients. However, although we did not measure oxalate levels, Tarng et al23 showed no significant increase in oxalate levels with intravenous vitamin C treatment. In conclusion, intravenous vitamin C is an effective adjuvant therapy to EPO in hemodialysis patients. It can be used in patients with normal iron status, as well as those with iron overload or functional iron deficiency. Further studies are needed to find out the mechanisms of this effect.

VITAMIN C AND EPO RESPONSE IN HEMODIALYSIS

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