**5. Conclusion**

For patients with chronic kidney disease who are not on dialysis, oral iron or IV iron can be used for iron supplementation. This conclusion is consistent with the opinion of the Work Group from K DOQI guidelines.

The preferred route of administration of iron in patients with chronic kidney disease on hemodialysis is intravenous as supported by K DOQI guidelines as of 2006.

#### **6. Ascorbic acid**

Vitamin C or ascorbic acid has been studied in the metabolism of iron and anemia management. The first studies were performed in guinea-pigs. It was found that ascorbic acid deprivation increased the total non-haem iron concentration in the spleen and reduced it in the liver, and in both organs ferritin was diminished and haemosiderin increased. Repleting the ascorbic acid restored the normal distribution of iron between the two storage compounds, and in the spleen the total storage iron concentration returned to control levels within 24 hours.**21** Another important property of ascorbic acid is its ability to increase the availability of storage iron to chelators.**22** In hemodialysis patients this role of ascorbic acid was investigated by Deicher who conducted a cross-sectional, single-centre observational study. Pre-dialysis plasma Vitamin C concentrations were measured and response to EPO (Hb concentration/ international units EPO/kg/week) was recorded. Univariate analysis yielded a significant correlation between Vitamin C plasma levels and response to EPO. It was found that in unselected hemodialysis patients Vitamin C plasma levels account, at least partially for the response to EPO.**23** That work led to ascorbic acid investigations for use in EPO-treated hemodialysis patients, particularly those with EPO- hypo responsiveness, elevated serum ferritin levels, and functional iron deficiency (transferrin saturation ≤20 percent and elevated ferritin level between 200 to 800 ng/ml or higher). Studies evaluated the role of IV Vitamin C in hemodialysis patients and showed that in those patients who develop resistance to EPO with "functional iron deficiency", the resistance can be overcome by giving Vitamin C instead of iron,thus avoiding hemosiderosis.**24** In another comparative larger study, Tarng et.al. were able to show similar results in a prospective trial of dialysis patients. Sixty-five HD patients with serum ferritin levels greater than 500 mcg/L were recruited and divided into the control (N = 19) and intravenous ascorbic acid IVAA (N = 46) groups. IVAA patients with a hematocrit (HCT) of less than 30% received 300 mg of ascorbic acid three times per week for eight weeks. Controls had a HCT of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy. Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in Hb and reticulocyte index and a concomitant 24% reduction in EPO dose after eight weeks. This paralleled a

daily for 21 days (n = 116). Ferumoxytol resulted in a mean increase in Hb of 1.02+/-1.13 g/dL at day 35 compared with 0.46+/-1.06 g/dL with oral iron (p = 0.0002). There was a greater mean increase in TSAT with ferumoxytol compared with oral iron at day 35 (p <

For patients with chronic kidney disease who are not on dialysis, oral iron or IV iron can be used for iron supplementation. This conclusion is consistent with the opinion of the Work

The preferred route of administration of iron in patients with chronic kidney disease on

Vitamin C or ascorbic acid has been studied in the metabolism of iron and anemia management. The first studies were performed in guinea-pigs. It was found that ascorbic acid deprivation increased the total non-haem iron concentration in the spleen and reduced it in the liver, and in both organs ferritin was diminished and haemosiderin increased. Repleting the ascorbic acid restored the normal distribution of iron between the two storage compounds, and in the spleen the total storage iron concentration returned to control levels within 24 hours.**21** Another important property of ascorbic acid is its ability to increase the availability of storage iron to chelators.**22** In hemodialysis patients this role of ascorbic acid was investigated by Deicher who conducted a cross-sectional, single-centre observational study. Pre-dialysis plasma Vitamin C concentrations were measured and response to EPO (Hb concentration/ international units EPO/kg/week) was recorded. Univariate analysis yielded a significant correlation between Vitamin C plasma levels and response to EPO. It was found that in unselected hemodialysis patients Vitamin C plasma levels account, at least partially for the response to EPO.**23** That work led to ascorbic acid investigations for use in EPO-treated hemodialysis patients, particularly those with EPO- hypo responsiveness, elevated serum ferritin levels, and functional iron deficiency (transferrin saturation ≤20 percent and elevated ferritin level between 200 to 800 ng/ml or higher). Studies evaluated the role of IV Vitamin C in hemodialysis patients and showed that in those patients who develop resistance to EPO with "functional iron deficiency", the resistance can be overcome by giving Vitamin C instead of iron,thus avoiding hemosiderosis.**24** In another comparative larger study, Tarng et.al. were able to show similar results in a prospective trial of dialysis patients. Sixty-five HD patients with serum ferritin levels greater than 500 mcg/L were recruited and divided into the control (N = 19) and intravenous ascorbic acid IVAA (N = 46) groups. IVAA patients with a hematocrit (HCT) of less than 30% received 300 mg of ascorbic acid three times per week for eight weeks. Controls had a HCT of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy. Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in Hb and reticulocyte index and a concomitant 24% reduction in EPO dose after eight weeks. This paralleled a

hemodialysis is intravenous as supported by K DOQI guidelines as of 2006.

0.0001).

**5. Conclusion** 

**6. Ascorbic acid** 

Group from K DOQI guidelines.

significant rise in serum iron and TSAT and a fall in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68+/-37 vs. 124 +/-64 mcg/dL, TSAT 27+/-10 vs. 48+/-19%, E-ZPP 123+/-44 vs. 70+/-13 micromol/mol heme, and serum ferritin 816+/-435 vs. 587+/-323 mcg/L, p<0.05). Compared with responders, mean values of Hb, EPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19).**<sup>25</sup>**

A single PO study by Benz et. al. was conducted in 21 EPO resistant 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, HCT, EPO dose, ferritin, and transferrin saturation were recorded at baseline and after three months of treatment. EPO dose/HCT was calculated. Serum oxalate levels were also measured. In this study, daily oral ascorbic therapy decreased ferritin levels and EPO dose requirements while raising Hb and HCT level. 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), and 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) Patients with oxalate levels >27 micromol/L were instructed to stop ascorbic acid treatment, and mean levels decreased from 107 to 19 micromol/L (*p =* 0.01) over a mean time of 71 days. This beneficial profile of the effects of ascorbic acid therapy is consistent with improvement of EPO resistance and cost savings in this population.**<sup>26</sup>**

The primary concern for using Vitamin C in dialysis patients is secondary oxalosis because of the impairment in renal excretion and inadequate removal by dialysis procedures.**27-28** Tarng et.al. showed that oxalate levels increase modestly after 8 weeks of IV Vitamin C but information on longer courses of treatment is limited.**25** Canavese prospectively studied the dose of Vitamin C and effect on oxalate levels in 30 dialysis patients. Eighteen patients were administered intravenous ascorbate during 18 months (250 mg/wk, subsequently increased to 500 mg), and 12 patients were taken as reference untreated cases. The study found that plasma oxalate levels progressively increased as the dose of IV Vitamin C was increased from 250 to 500 mg/week. After six months at a dose of 500 mg per week, 7 of 18 patients (40 percent) attained plasma oxalate levels that exceeded the range that would be associated with calcium oxalate super saturation at usual calcium concentrations**.29**

The 2006 K/DOQI guidelines for anemia in CKD stated that there was insufficient evidence to recommend Vitamin C as an adjuvant to EPO therapy.**30** However, several of the clinical studies were published subsequent to the development of those guidelines.
