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J Am Soc Nephrol 15: 2486-2493, 2004
© 2004 American Society of Nephrology
doi: 10.1097/01.ASN.0000137884.59308.E7
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J Am Soc Nephrol 15:2486-2493, 2004
© 2004 American Society of Nephrology

CLINICAL SCIENCE

Effect of Intravenous Ascorbic Acid Medication on Serum Levels of Soluble Transferrin Receptor in Hemodialysis Patients

Der-Cherng Tarng*,{dagger}, Szu-Chun Hung*,{ddagger} and Tung-Po Huang*,{dagger}

*Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; {dagger}Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; and {ddagger}Division of Nephrology, Taoyuan Veterans Hospital, Taoyuan, Taiwan

Correspondence to Dr. Der-Cherng Tarng, National Yang-Ming University School of Medicine, and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. Phone: +886-2-2821-2458; Fax: +886-2-2826-1132; E-mail: dctarng{at}vghtpe.gov.tw


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
ABSTRACT. Intravenous ascorbic acid (IVAA) medication has been shown to facilitate iron release from inert depots and subsequently circumvent the defective iron utilization in chronic hemodialysis (HD) patients who are treated with recombinant human erythropoietin (rHuEPO). This study focuses on the effects of IVAA supplementation on serum concentrations of soluble transferrin receptors (TfR) on the basis of the hypothesis that an increase of labile iron in the cytosol will lead to inhibition of TfR expression. First, 138 HD patients were studied to evaluate the interrelation between serum TfR and iron status. In a stepwise multivariate analysis, serum EPO and transferrin saturation (TSAT) were the two independent predictors for serum TfR in HD patients (r2 = 0.510, P < 0.001). Further analyses showed that the lower the serum EPO and the higher the TSAT, the lower the serum TfR in HD patients who are on maintenance rHuEPO treatment. Second, 36 HD patients were recruited in a randomized, controlled study to receive IVAA (total dose of 2000 mg) or normal saline (placebo) medication. Serum levels of TfR, EPO, and ferritin and TSAT were measured at baseline and within 7 d after starting IVAA or placebo. There were no significant changes in serum EPO and ferritin levels in patients who received either IVAA (n = 18) or placebo (n = 18). Serum TfR levels (P < 0.001) significantly declined with a parallel rise in TSAT (P < 0.05) as compared with presupplemental values within 7 d in IVAA patients before any apparent alteration in hematocrit values, but the changes were not observed in the placebo group. The trend of decreased serum TfR and increased TSAT was similar in IVAA patients with ferritin of <500 µg/L or >500 µg/L. It is concluded that ascorbic acid status can significantly decrease serum TfR concentrations and increase percentage of TSAT, probably through alterations in intracellular iron metabolism.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
All cells have transferrin receptors (TfR) on their surface. In a normal adult, ~80% of the receptors are in the erythroid marrow (1). Therefore, the erythroid marrow is the main source of soluble TfR in plasma. Several lines of evidence have indicated that the direct relationship to the number of erythroid precursors makes soluble TfR assay the method of choice for evaluation of erythroid marrow activity in clinical settings. Indeed, serial measurements of TfR are useful for the quantitative assessment of erythropoietic activity in hemodialysis (HD) patients who are treated with recombinant human erythropoietin (rHuEPO) (2,3) and for monitoring the hemoglobin response to rHuEPO therapy (4). The body iron status is the second major determinant of soluble TfR, and circulating receptor levels rise in the iron-depleted status as a result of the posttranscriptional modification of TfR mRNA expression in the erythroid precursors (5). However, information on the specificity of serum TfR for detection of iron-deficient erythropoiesis in HD patients is conflicting. The main cause for this is that rHuEPO-enhanced erythropoiesis is a major confounder in evaluating the interrelation between TfR and iron deficiency. For practical purposes, interpretation of elevated TfR levels require evaluation of body iron status to distinguish between iron-deficient erythropoiesis and increased erythroid mass. Therefore, in the present study, we first assessed the respective role of iron status and EPO stimulation on serum TfR levels in HD patients by a simultaneous measurement of serum TfR and EPO levels and iron metabolism indices (ferritin and transferrin saturation [TSAT]).

A large body of evidence has indicated that vitamin C (ascorbic acid; ascorbate) is involved in several phases of iron transport, as well as the regulation of iron uptake and sequestration (6–10). At the molecular level, ascorbic acid mobilizes iron from the ferritin crystal core in vitro by reducing ferric iron (Fe3+) to ferrous iron (Fe2+) (6). Intracellularly, ascorbic acid facilitates the enzymatic incorporation of iron into protoporphyrin for heme synthesis (7) and enhances iron-induced translation of ferritin by promoting the conversion of the iron regulatory protein (IRP) RNA binding form to aconitase (8). In human, oral administration of ascorbic acid augments the absorption of non-heme iron from the diet (9). Moreover, individuals with iron overload generally have low plasma levels of ascorbic acid, possibly as a result of increased vitamin oxidation catalyzed by iron (10). Patients who receive maintenance HD are at high risk for vitamin C deficiency, and systemic supplementation of ascorbic acid is recommended (11,12). Recent therapeutic approaches based on intravenous administration of ascorbic acid (IVAA) have received increasing attention in most HD units to promote an increase of iron utilization, as well as better anemia control (13–16). The beneficial effect on rHuEPO response can be observed for HD patients who have a high ferritin level of >500 to 800 µg/L (13–15) and even for those with normal iron status (16).

The amount of chelatable intracellular iron affects the stability of TfR mRNA (17). In the states of iron abundance, cytoplasmic IRP has aconitase activity and does not bind to iron-responsive elements, producing increased TfR mRNA degradation (18). Therefore, in contrast to the deprivation of intracellular iron, an increase of labile iron in the cytosol will result in inhibition of TfR expression. Because ascorbic acid facilitates iron mobilization from inert iron depots and increases bioavailable intracellular iron for erythroid progenitors (13–16), the resulting increase in iron availability would be expected to cause a downregulation of TfR expression. Thus, the aim of the present study was to investigate whether IVAA would decrease serum TfR levels in HD patients. The doses of rHuEPO are kept constant during the study period to preclude the effect of rHuEPO on erythropoiesis and subsequently on TfR levels.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
The study contained two parts: A cross-sectional observation and then a prospective investigation. The first portion of the study was to evaluate the interrelation between serum TfR levels and iron status in HD patients. We recruited 138 patients (76 men and 62 women) who were undergoing chronic HD at three dialysis units of the affiliated Hospital of National Yang-Ming University. They were 56 ± 14 yr of age and had been on dialysis for 53 ± 48 mo. The diagnoses of ESRD included glomerulonephritis (n = 40), interstitial nephritis (n = 12), hypertension (n = 13), diabetes (n = 32), systemic lupus erythematosus (n = 12), and shrunken kidneys of unknown cause (n = 29). Inclusion criteria were age >20 yr, duration of previous dialysis >6 mo, time on rHuEPO therapy >6 mo, and rHuEPO dose and hematocrit (HCT) values stable for 3 mo before enrollment. Patients were excluded when the following events occurred in the preceding 4 wk: bleeding; hemolysis; liver diseases; infections; red blood cell transfusions; and medications, including oral or intravenous iron supplementation, oral or intravenous ascorbic acid supplementation, angiotensin-converting enzyme inhibitors, and theophylline. All patients were dialyzed for 4 h thrice a week, using a single-used dialyzer (Nipro, Nissho, Japan) with 1.5-m2 effective surface area of cellulose diacetate membrane, blood flow of 250 to 350 ml/min, and dialysate flow of 500 ml/min. They were constantly treated with epoetin {beta} (Roche Diagnostics, Mannheim, Germany), and the mean maintenance dose was 79 ± 33 U/kg weekly (range, 13 to 193 U/kg per wk) given subcutaneously in one to three doses. For evaluating serum TfR and EPO response to anemia in HD patients, samples were obtained from 25 anemic reference subjects (14 men and 11 women; mean age, 59 ± 14 yr) who had HCT <38% as a result of hemolytic (n = 9) and dyserythropoietic (n = 16) anemia and had not received red blood cell transfusions in the preceding 4 wk. Reference subjects with creatinine clearance of <100 ml/min were of course excluded from the reference group. Blood samples were drawn from fasting reference subjects or in HD patients after an overnight fast (≥86 h after the last dose of rHuEPO).

The second portion of the study was conducted to assess the patterns of change in serum TfR and EPO, as well as iron metabolism indices after intravenous administration of ascorbic acid in HD patients. Thirty-six patients (15 men and 21 women; mean age, 57 ± 17 yr) who were undergoing chronic HD in the dialysis unit of Taoyuan Veterans Hospital participated in the study. The inclusion and exclusion criteria for patient selection were the same as those in the first portion of the study. The randomized, placebo-controlled study was carried out for 7 d. In the 7-d period, 36 HD patients were randomly assigned to receive supplementation with ascorbic acid (IVAA) or normal saline (placebo). Treatment order is block-randomized with the use of computerized-generated random numbers. After baseline blood samples were obtained, 100 ml of sodium ascorbate (total vitamin C, 1000 mg) or 100 ml of 0.9% sodium chloride was infused intravenously for 30 min after dialysis at two consecutive HD sessions (e.g., one dose given in the third session of a week and another given in the fist session of the subsequent week). For minimizing the erythropoietic stimulation on the TfR levels, rHuEPO was continued without changes in dosage during the study. All patients were also required to complete a 3-d food diary (19), which was used to estimate the daily intake of vitamin C before the investigation. Blood samples were taken on three occasions, before the first IVAA medication started (day 0, baseline), before the second dose started (day 3), and on the seventh day of the study (day 7). All patients fasted for at least 8 h immediately before the blood samples were taken. The study protocol was approved by the local ethics committee, and informed consent was obtained from each of the study subjects.

Laboratory Measurements
After collection, blood samples were centrifuged immediately at 800 x g and 4°C for 10 min, and the serum was stored in 500-µl aliquots at –70°C until assay. Each sample was run in duplicate for all assays. HCT was measured using the Technicon H*2 hematology analyzer (Bayer Diagnostics, Tarrytown, NY). Serum iron concentration was determined by an autoanalyzer (Hitachi 736-60, Naka, Japan) using a colorimetric method, TIBC by the TIBC Microtest (Daiichi, Tokyo, Japan), and serum ferritin by RIA kit (DiaSorin, Stillwater, MN). Percentage of TSAT was calculated by dividing serum iron concentration by TIBC x 100. TSAT determination showed good analytical reproducibility with the intra-assay and interassay coefficients of variance of low standard <6.5% and of high standard <3.9%, respectively. Serum EPO concentration was measured by RIA kit (Incstar, Stillwater, MN), using 125I-labeled rHuEPO as the tracer; a goat anti-human EPO as the primary antibody; a donkey anti-goat IgG antiserum as the second antibody; and the rHuEPO standards at 0, 5, 10, 25, 50, 100, and 200 mU/ml. Serum EPO values ranged from 4.9 to 52.7 mU/ml in healthy individuals (n = 104) described by the manufacturer. The minimum detectable level was <4.4 mU/ml. Plasma TfR concentration was measured by ELISA kit (R&D Systems, Minneapolis, MN) according to the procedure recommended by the manufacturer. The 2.5 to 97.5th percentiles distribution of this TfR assay was 740 to 2390 µg/L in healthy individuals (n = 225) described by the manufacturer. The minimum detectable level was <0.5 nmol/L (42.3 µg/L). The reproducibility of these two assays was good. The intra-assay and interassay coefficients of variance of low standard were <6.4% for EPO assay and <7.7% for TfR assay and of high standard were <5.8% for EPO assay and <6.7% for TfR assay, respectively.

Statistical Analyses
Statistical analysis was performed using the computer software SPSS 11.0 (SPSS, Chicago, IL). Data are expressed as means ± SD. Serum ferritin values were reported as median and range because the data were not normally distributed. In study 1, for comparison of two groups, t test was used for normally distributed variables and Mann-Whitney rank sum test for variables with nonnormal distribution. Pearson’s {chi}2 test was used for frequency measures. Univariate analysis was performed using Pearson correlations. A stepwise multiple regression analysis was used to identify the independent predictors of TfR levels. Independent variables included age, gender, HD duration, serum EPO, serum ferritin, TSAT, weekly rHuEPO dose, HCT, and factors that pertain to rHuEPO response (e.g., C-reactive protein, serum intact parathyroid hormone, aluminum levels). Only the equations in which all coefficients differed from zero at the 5% level were retained. In study 2, laboratory measurements that were performed at multiple times after IVAA or placebo treatment were analyzed using ANOVA for repeated measures. When the time effect was statistically significant, post hoc contrasts were performed for each time point (day 3 versus baseline and day 7 versus baseline) using the Scheffe test. The assessment of treatment effect (IVAA versus placebo) was indicated by the treatment x time interaction coefficient. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Study 1: Determinants of Soluble TfR in HD Patients
Mean values of HCT, serum TfR, serum EPO, and TSAT, as well as median value of serum ferritin, in 25 reference subjects were 29.4 ± 5.5%, 4386 ± 2604 µg/L, 142 ± 191 mU/ml, 24 ± 15%, and 125 µg/L (10 to 1164), respectively. Characteristics of 138 HD patients who were recruited in the cross-sectional study are summarized in Table 1. HD patients were similar to reference subjects with respect to age, gender, and HCT levels (P > 0.05). As expected, anemia of HD patients was characterized by defective EPO production and secondary bone marrow hypoproliferation. Mean values of serum TfR and EPO in HD patients were significantly lower (P < 0.001), whereas median value of serum ferritin and mean TSAT were higher (P < 0.001) than those in reference subjects. Furthermore, serum TfR levels were significantly lower in HD patients with TSAT ≥20% than in those with TSAT <20% (1391 ± 317 versus 1783 ± 573 µg/L; P < 0.001). Likewise, HD patients with serum ferritin ≥100 µg/L had significantly lower serum levels of TfR (1424 ± 374 versus 1665 ± 462 µg/L; P < 0.05) and EPO (19.8 ± 12.1 versus 32.7 ± 24.3 mU/ml; P < 0.001) as compared with those with serum ferritin <100 µg/L (Table 1). Univariate analysis shows that serum TfR levels correlated positively with serum EPO (P < 0.001) and weekly rHuEPO dose (P < 0.05) but inversely with serum ferritin (P < 0.001) and TSAT (P < 0.001) in HD patients (Table 2). Instead of the expected inverse relationship between HCT and TfR levels, there was a positive correlation between these two parameters (P < 0.05). Stepwise multiple regression analysis revealed that serum EPO and TSAT were the two independent predictors of TfR levels (Table 3). Overall, the model explained 51% of the variability in serum TfR (r = 0.714, P < 0.001).


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  		Table 1. Characteristics of hemodialysis patients recruited in the cross-sectional studya
 

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  		Table 2. Univariate analysis of the relationships between serum soluble transferrin receptor or erythropoietin level and potentially explanatory variablesa
 

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  		Table 3. Independent predictors of serum soluble TfR levelsa in chronic HD patients (n = 138)
 
Study 2: Effect of IVAA on TfR Levels
Eighteen patients were randomly assigned to receive IVAA medication and another 18 patients to receive placebo. Among 36 HD patients, 22 patients had ferritin of <500 µg/L (12 in IVAA group and 10 in placebo group) and 14 patients had ferritin of >500 µg/L (six in IVAA group and eight in placebo group). Patients who were treated with vitamin C or placebo did not differ significantly from each other in terms of age, gender distribution, duration of HD, causes of chronic renal failure, daily intake of vitamin C, and weekly rHuEPO dose, as well as mean values of serum TfR, EPO and ferritin, TSAT, and HCT (Table 4). Mean serum concentrations of TfR significantly decreased from day 0 to day 7 in patients in the IVAA group (1637 ± 484 µg/L on day 0 versus 1374 ± 563 µg/L on day 3 or 1244 ± 601 µg/L on day 7; P < 0.001 by post hoc Scheffe test; P < 0.001 for both repeated measures ANOVA and the treatment x time interaction), whose rHuEPO doses and HCT values were maintained constant (Figure 1). There were no significant changes in mean serum levels of EPO and ferritin for 7 d (EPO: 25.3 ± 16.6 mU/ml on day 0 versus 24.3 ± 12.3 mU/ml on day 7, P > 0.05; ferritin: 491 ± 300 µg/L on day 0 versus 428 ± 262 µg/L on day 7, P > 0.05). The change in serum TfR had no correlation with baseline serum ferritin level (r = –0.153, P > 0.05). Conversely, when compared with baselines, TSAT significantly increased on day 7 after a total IVAA dose of 2000 mg (27 ± 9% on day 0 versus 32 ± 12% on day 7, P < 0.05 by post hoc Scheffe test; P < 0.01 for both repeated measures ANOVA and the treatment x time interaction). The decrease in serum levels of TfR and increase in TSAT were also observed in two IVAA subgroups with ferritin of <500 or >500 µg/L (Figure 1). In patients in the placebo group or in the two subgroups stratified by a ferritin cutoff value of 500 µg/L, no significant changes were noted in the mean serum concentrations of TfR, EPO, and ferritin, as well as TSAT, for 7 d (Figure 2).


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  		Table 4. Characteristics and baseline laboratory data of chronic HD patients who received vitamin C or placebo in the randomized controlled study
 


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  		Figure 1. Effects of intravenous ascorbic acid (IVAA) medication on the mean concentrations of soluble transferrin receptor (TfR), serum erythropoietin, serum ferritin, and percentage saturation of transferrin in all patients (n = 18;{U25A9}) and two subgroups of patients with ferritin of <500 µg/L (n = 12; {square}) and of >500 µg/L (n = 6; {blacksquare}) for 7 d. Brackets indicate SD. aP < 0.001, bP < 0.01, and cP < 0.05 versus baselines (day 0) by ANOVA for repeated measures, followed by pairwise multiple comparison.

 


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  		Figure 2. Effects of placebo on the mean concentrations of soluble TfR, serum erythropoietin, serum ferritin, and percentage saturation of transferrin in all patients (n = 18; {U25A9}) and two subgroups of patients with ferritin of <500 µg/L (n = 10; {square}) and of >500 µg/L (n = 8; {blacksquare}) for 7 d. Brackets indicate SD.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The current study showed that the lower the serum EPO and the higher the TSAT, the lesser the serum TfR in HD patients on who are on maintenance rHuEPO therapy. Besides, serum TfR levels positively correlated with the dose of administered rHuEPO and HCT levels (Table 2). After adjustment for the other variables, serum endogenous EPO and TSAT are two independent determinants of serum soluble TfR. Our data confirmed that serum TfR levels quantitatively reflect the integrated effects of EPO endogenous production and iron availability in HD patients (2–4,13–16) and corroborated the previous investigations by Bovy et al. (20).

The present study confirmed that serum endogenous EPO levels vary widely in anemic HD patients and have no correlation with HCT levels (21). It indicates that the adaptation of EPO levels to HCT values is lost in ESRD patients, and factors other than tissue hypoxia are physiologically involved in the regulation of EPO production. Evidence has been presented for a higher serum EPO level in ferropenic HD patients (ferritin <50 µg/L) as compared with those with normal iron stores (22). We also found that there is an inverse correlation between serum EPO and ferritin levels (Table 2). There are two possible explanations for this. One is that EPO and ferritin levels are reciprocally associated with duration on dialysis. That is, ferritin levels increase with dialysis duration as a result of inflammation, infections, and iron supplementation, whereas EPO levels independently fall with dialysis duration as remnant renal mass decreases. In such a situation, the link between ferritin and EPO is not causal. The other possibility is that low intracellular iron levels sustain hypoxia-mediated EPO production by remnant EPO-producing cells. In brief, the so-called hypoxia switch mechanism involves two hydroxylases, which are inactivated by hypoxia and lead to HIF-1{alpha}–mediated expression of a number of genes, including EPO. The two hydroxylases are iron-dependent enzymes: Iron deprivation leaves the switch on, whereas, in the absence of iron deprivation, switch activation quickly enhances iron acquisition by the cell, leading to enzyme activation so that the "switch" turns off (23–25). The latter mechanism would explain a significant fall in serum EPO observed within 2 wk after starting intravenous iron treatment in HD patients with iron deficiency, before any apparent change in hemoglobin concentration (22). Recently, reactive oxygen species have been shown to suppress in vitro gene expression and production of EPO (26). Jelkmann et al. (27) demonstrated that EPO secretion significantly increases in kidneys when vitamins A, E, and C in combination are added to the perfusion medium. In contrast, we did not found any significant change in serum EPO concentrations for 7 d after IVAA medication as compared with the presupplemental values. The lack of observed effect of ascorbate on EPO levels most likely results from a lack of reserve EPO production in chronic HD patients.

TSAT indicates a balance between supply and demand of plasma iron. TSAT has wide fluctuations as a result of a diurnal variation in serum iron and transferrin affected by the nutritional status. Nevertheless, a series of follow-ups are crucial for TSAT to act as an index of iron availability during the study period. In the scorbutic animals (28) and the Bantu with scurvy (29), defective iron utilization related to ascorbate deficiency is indicated by diminished plasma iron and increased free erythrocyte protoporphyrin. Moreover, Wapnick et al. (30) reported that serum iron levels increased dramatically after oral administration of vitamin C to iron-loaded scorbutic subjects. In our study, TSAT increased significantly 7 d after administration of IVAA to HD patients with ferritin either <500 µg/L or >500 µg/L (Figure 1). Our findings are in keeping with the recent studies indicating that IVAA medication improved hemoglobin response to rHuEPO accompanied by a rise in TSAT and serum iron for HD patients who have both normal and increased iron stores (13–16). The concrete evidence supports this contention that vitamin C may in some manner increase intracellular chelatable iron by facilitating the iron mobilization from the ferritin compartment and labile plasma iron pool (31) and enhancing cellular uptake from low molecular weight iron complexes (32).

The most compelling observation of this study is that circulating TfR concentrations declined significantly after IVAA supplementation as compared with placebo administration. rHuEPO-enhanced erythropoiesis, which itself raises serum receptor levels, is a major confounder in evaluating the association between TfR and iron status. If one intends to prove that a decrease in serum TfR levels is caused by an increase in iron availability and utilization, then this decrease should be accompanied by an increase in TSAT or serum ferritin with no change in hemoglobin or reticulocytes. Accordingly, in the present study, the unique study design, different from the previous studies (13–16), merits emphasis. First, the dosage of rHuEPO administered was kept constant during the study to minimize its erythropoietic stimulation on TfR levels. Second, the outcome of our study aimed at the change in serum TfR concentrations, not the erythropoietic response to rHuEPO after IVAA supplementation. The response rate ranged from 49 to 67% of HD patients who received IVAA supplementation in the studies of Tarng et al. (15) and Keven et al. (16). IVAA responders had a significant rise in hemoglobin levels and a reduction in rHuEPO dose or rHuEPO-hemoglobin ratio at the study period of 8 wk to 6 mo. In contrast, without significant change in serum EPO level and the rHuEPO dosage in our study, a significant decrease in serum TfR concentrations paralleled a concomitant rise in TSAT within 7 d after starting IVAA medication, before any noticeable change in HCT level. The present findings are consistent with our hypothesis that an increase in cytosolic nonstorage iron induced by IVAA medication would then facilitate TfR downregulation through the IRP mechanism (8,17,18).

The limitation of the present study is that we cannot directly assess intracellular iron metabolism and correlate the posttranscriptional modification of TfR with the changes in serum concentrations of TfR. Moreover, long-term safety of IVAA has not been examined, particularly from the standpoint of oxalate levels or oxidant stress. Of course, the same is also true for oral ascorbate therapy. Subclinical vitamin C deficiency is frequently encountered in chronic HD patients as a result of insufficient intake from diet (33) and loss during dialytic procedures (34). Tissue concentration of ascorbic acid is further decreased in HD patients, perhaps as a result of increased vitamin oxidation catalyzed by the exaggerated oxidative stress and iron-overloaded states (35,36). Because the need for vitamin C is increased in HD patients, supplementation of ascorbic acid is essential. Currently, in the case of suspected vitamin C deficiency, 1.0 to 1.5 g/wk oral ascorbate for chronic HD patients or 300 to 500 mg of parenteral ascorbate per dialysis session is recommended (11,12). However, prescription of vitamin C in different dialysis facilities varies between 55 and 1000 mg daily (37–39). For assessing the acute changes in serum levels of TfR, a high IVAA bolus dose of 1000 mg administered after each dialysis session was chosen in the present study. Our data indicate that ascorbic acid medication can increase percentage of TSAT and significantly decrease serum TfR concentrations, probably through alterations in intracellular iron metabolism.


   Acknowledgments
 
This study was supported by the National Science Council (grant NSC 92-2314-B-010-027) and Taipei Veterans General Hospital Research Program (grants VGH-89-256 and VGH-93-222), respectively.

We are extremely grateful to P.C. Lee for expert secretarial assistance and graphic designs.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication March 14, 2004. Accepted for publication June 19, 2004.




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