Beneficial Hematologic Effects of Daily Oral Ascorbic Acid Therapy in ESRD Patients with Anemia and Abnormal Iron Homeostasis: A Preliminary Study

Abstract

Aim. To determine the efficacy and effects of the oral administration of ascorbic acid on anemia management in ESRD patients with hyperferritinemia. Methods. Twenty-one anemic hemodialysis patients with ferritin levels greater than 350 ng/mL had received oral daily ascorbic acid at a dose of 500 mg/day and were retrospectively studied. Hemoglobin, hematocrit, EPO dose, ferritin, and transferrin saturation were recorded at baseline and after three months of treatment. EPO dose/hematocrit was calculated. Serum oxalate levels were also measured. Results. Hb increased 9% from 11.4 to 12.2 gm/dL (p = 0.05), HCT increased 10% from 33.3 to 36.7% (p = 0.05), but EPO dose requirement decreased 33% from 26,229 to 17,559 U/week (p = 0.03). Ferritin levels decreased 21% from 873 to 691 ng/mL (p = 0.004). Mean oxalate level during therapy was 87 umol/L (normal <27). Patients with oxalate levels >27 umol/L were instructed to stop ascorbic acid treatment, and mean levels decreased from 107 to 19 umol/L (p = 0.01) over a mean time of 71 days. Conclusion. In this study, daily oral ascorbic therapy decreased ferritin levels and EPO dose requirements while raising hemoglobin and hematocrit level. This beneficial profile of effects of ascorbic acid therapy is consistent with improvement of EPO resistance and cost savings in this population.

Keywords:

• anemia, ESRD
• ferritin
• EPO
• vitamin C
• ascorbic acid

INTRODUCTION

Iron homeostasis is frequently disrupted in ESRD patients with resultant hyperferritinemia. Ferritin levels greater than 350 ng/mL are commonly found in anemic ESRD patients and can be associated with detrimental effects at these high levels.[1–6] Elevated ferritin levels may have multiple causes resulting from IV iron administration, dysfunctional nutritional status, and inflammation leading to an efflux of cellular ferritin.[7–9] Anemic ESRD patients, who are refractory to treatment with erythropoietin (EPO resistant or hyporesponsive) and/or iron therapy, commonly have elevated ferritin levels.[10–13]

The administration of intravenous ascorbic acid (vitamin C) has been reported to an effective treatment for anemia and abnormal iron homeostasis. Ascorbic acid has resulted in increased serum iron in patients with scurvy who have anemia, decreased serum iron, and increased iron stores.[14] The use of ascorbic acid has also been used as an adjuvant therapy to reduce hyperferritinemia and improve anemia in dialysis patients.[3],[4],[15–18]

Ascorbic acid may correct the derangements of iron homeostasis that lead to reticuloendothelial system (RES) iron overload, anemia, and EPO resistance by maintaining iron in the reduced state as well as potentiating the enzymatic incorporation of iron into protoporphyrin in chickens.[19] In guinea pigs, ascorbic acid deficiency has been shown to increase the amount of iron stored as hemosiderin.[20] This form of iron is less soluble and therefore less available for erythropoiesis. The correction of the ascorbic acid deficiency reduces hemosiderin levels. In vitro, ascorbic acid slows the conversion of ferritin to hemosiderin.[21]

The purpose of this study is to examine the effects of oral, daily ascorbic acid on anemia and iron management in ESRD patients with anemia and hyperferritinemia.

METHODS

Patients

For demographic and baseline laboratory data, see Table 1.

Table 1 Baseline data

Demographic characteristics		Range
Number	19
Mean age (years)	71	46–88
Gender (M/F)	14/5
Baseline data	Mean	Range
Hemoglobin (gm/dL)	11.4	9–13.6
Hematocrit (%)	34.3	27–40.8
EPO dose (units/wk)	26,229	767–59,800
Ferritin (ng/mL)	873	354–2136
Transferrin saturation (%)	22	11–38
Intact PTH (pg/mL)	390	19–1478
URR (%)	75	67–86

Study Design

Twenty-one anemic hemodialysis patients with ferritin levels greater than 350 ng/mL had received oral daily ascorbic acid (500 mg) and were retrospectively studied for changes in iron profile, hemoglobin, and EPO responsiveness. All patients were on a multivitamin that contained 100 mg of ascorbic acid. Two patients with active infections were excluded due to the effect of acute inflammation on the parameters being studied. The excluded patients included one patient with pneumonia and one patient with osteomyelitis. Baseline characteristics of the 19 remaining patients in the study group are detailed (see Table 1). Complete EPO dose administration was available for 18 patients.

Patient charts and laboratory data were reviewed. All patients were on hemodialysis for at least three months. Ferritin, Hb/HCT, EPO dose, intact PTH, and transferrin saturation were recorded at baseline and after three months of treatment. EPO dose was adjusted according to the In-Center EPO and Iron Protocol of the Wynnewood Hemodialysis Unit (see Table 2). EPO dose was decreased if HCT was greater than 36%, and the three-month average HCT was >37.5%. Serum oxalate levels were also measured.

Table 2 Anemia management protocol

Laboratory Measurements

Hb/HCT, transferrin saturation, and ferritin levels values were performed by the Renal Lab Division of Renal Care Group. Serum oxalate specimens were refrigerated at 4°C, and analysis was performed by National Medical Services in Willow Grove, Pennsylvania.

Statistical Measurements

The mean percent change for Hb/HCT, erythropoietin dose, and ferritin were calculated. Student t-tests were used to compare the changes in these parameters. The Wilcox Signed Ranks test was used to compare changes in the EPO/HCT ratio.

RESULTS

See Table 3 for primary results, with Figure 1 depicting the main results graphically. Ascorbic acid therapy was found to have a statistically significant effect on all study parameters.

Table 3 Outcomes summary

Parameters	Baseline	Three months of ascorbic acid Tx	% Change	p
Hb (gm/dL)	11.4	12.2	9%	<0.05
HCT (%)	33.3%	36.7	10%	<0.05
Mean EPO dose (units/week)	26,229	17,559	33%	<0.03
Mean ferritin levels (ng/mL)	873	691	21%	<0.004
Mean EPO dose/HCT (ratio)	254	161	36%	<0.01

Figure 1. Hematologic parameters pre- vs. post-ascorbic acid therapy. *Denotes significant change.

After further analysis, excluding four patients who received 1 gram of IV iron during the study period, the decreases in ferritin (960 to 698 ng/mL, p = 0.001; 27.3% reduction) and EPO dose (28,536 to 18,614 U/week, p = 0.03; 34.8% reduction) remained statistically significant. Transferrin saturation and iPTH did not change. EPO dose decreased in 10 patients (52.6%). Ferritin levels decreased in 16 patients (84.2%; see Figure 2). Ferritin levels did not increase in three of four patients who received intravenous iron.

Figure 2. Changes in whole group ferritin pre- and post-ascorbic acid therapy.

Oxalate levels were measured in 13 patients. Mean oxalate level achieved during daily ascorbic acid therapy was 87 umol/L (normal <27). Ten patients with oxalate levels >27 umol/L were instructed to discontinue ascorbic acid treatment. Of those, seven patients complied, and mean levels decreased from 107 to 19 umol/L (p = 0.01) over a mean time of 71 days.

DISCUSSION

Orally administered ascorbic acid in this study was found to have a statistically significant effect on hematologic parameters and EPO responsiveness in anemic hemodialysis patients with hyperferritinemia. Oral ascorbic acid therapy reduced ferritin levels in patients with iron overload while hemoglobin levels were maintained or improved with lower EPO dose requirements. Ascorbic acid therapy in this population appears to have prevented ferritin levels from rising in the majority of patients treated with intravenous iron, while improvement in hemoglobin and hematocrit did occur.

The biochemical properties of ascorbic acid may explain the measured effects on iron homeostasis observed in this study. Patients with high ferritin levels have been shown to have hepatosplenic iron overload but marrow iron depletion.[22] Ascorbic acid may improve erythropoiesis in this high ferritin state by facilitating iron release from reticuloendothelial stores and mediating iron incorporation into protoporphyrin.

Oral ascorbic acid may be considered as an alternative route of administration to IV administration. IV administration of ascorbic acid in patients with hyperferritinemia has been demonstrated to decrease ferritin levels and EPO dose requirements and increase hemoglobin levels, as demonstrated by oral therapy in the present study.[4],[15–18] However, IV administration of ascorbic acid is laborious and costly. Oral administration may be limited by the rate of gastrointestinal absorption in ESRD patients. Oral ascorbic acid can also have a systemic effect.[15] In hemodialysis patients, secondary oxalosis is a potential concern of therapy. Ascorbic acid is metabolized into oxalate, which is excreted by the kidney. Increased oxalate can deposit in the heart and blood vessels. In this study population, oxalate levels during treatment were elevated. However, oxalate levels decreased to normal when the supplemental ascorbic acid was discontinued. These results indicate that oxalate levels should be monitored during oral ascorbic acid therapy.

The potential significance of this study is limited by the small sample size, its retrospective design, and the lack of a control group. All patients in the hemodialysis unit with ferritin levels greater than 350 ng/mL received ascorbic acid. Therefore, a control group was not available for study.

EPO resistance is often noted in hemodialysis patients with abnormal iron homeostasis. In the group studied here, EPO dose was reduced by 33% after three months of oral ascorbic acid therapy, while hemoglobin values rose by 10%. Additionally, EPO/HCT ratio fell by 36.6%. Decreases in EPO resistance may allow for a reduction in EPO dose requirements. High EPO dose requirements have been reported to be associated with an increased mortality.[23]

High EPO doses are more costly. The average EPO dose reduction in this population was 8,670 units/wk and represented a significant cost reduction. Based on a cost of $10.30/1000 U of EPO, the savings for these 19 patients was $1,697/week after three months of ascorbic acid treatment. This EPO dose reduction for this group of patients would translate into a cost savings of $88,229 annually.

Before oral ascorbic acid can be used more widely as a therapy for anemia associated with EPO resistance or hypo response, the appropriate treatment group will need to be determined. Ferritin can be elevated due to supplemental iron administration, inflammation, and/or malnutrition. This study did not address if patients with these different underlying causes of ferritin increase benefit equally. Patients with known acute inflammation were excluded. In addition, the minimum effective dose of ascorbic acid and the therapeutic index at this dose need to be determined. Ascorbic acid levels are affected by dietary and supplemental intake, consumption by uremia-induced oxidative stress, and loss of this water-soluble vitamin through dialysis membranes.[16],[24] Due to these factors, ESRD patients may or may not need higher serum levels to reduce EPO resistance or hypo response.[25]

In conclusion, this preliminary study has demonstrated that the use of daily oral ascorbic acid therapy improves hyperferritinemia, EPO resistance, and anemia, reducing EPO requirements by one-third. Oral ascorbic acid treatment may be a clinically effective and a cost-saving alternative to IV ascorbic acid administration. Further study with a randomized, prospective, double-blind protocol appears warranted to assess safety and dosing optimization.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

ACKNOWLEDGMENTS

Portions of this study were presented in abstract form at the annual meeting of the American Society of Nephrology, November 2005, Philadelphia, Pa.

The authors wish to thank Dr. Mark Pressman for critically reviewing this manuscript and for his insightful contributions. The authors also wish to thank Loretta Rossino and the Editorial Office of the Lankenau Institute for Medical Research for editorial assistance.