Oral use of iron with vitamin C in hemodialyzed patients☆☆☆

Patients and methods 

Twenty-four stable hemodialyzed patients were investigated. Causes of chronic renal failure were chronic glomerulonephritis in 15 patients, chronic tubulointerstitial nephritis in 6 patients, and analgesic nephropathy in 3 patients. Mean age was 49 ± 5 years, among them were 12 men and 12 women. The duration of hemodialysis treatment was from 6 months to 5 years. Twelve hemodialyzed patients were treated in the Dialysis Unit of Nephrological Clinic, University Hospital of L.Pasteur, Košice, and 12 hemodialyzed patients were treated in the Dialysis Unit of Internal Clinic, District Hospital, Nové Zámky, Slovak Republic. The duration of hemodialysis treatment was from 6 months to 5 years.

Before the beginning of the clinical study, all hemodialyzed patients were on free protein diet with the restriction of fruit and vegetables. Every patient underwent hemodialysis treatment 4 hrs/3 times/wk. Mean value of Kt/V was 1.51 ± 0.14. The investigated patients were treated by subcutaneous administration of r-HuEPO 3 times/wk; ferrous sulphate was administered intravenously.3 Pyridoxine (20 mg/d), folic acid (5 mg/wk) and vitamin C (50 mg/d) were administered orally.

During the clinical study, hemodialysis treatment was the same. Every patient was treated by r-HuEPO and received pyridoxine 20 mg/d orally, folic acid 5 mg/wk, and calcium carbonate 3 g/d as a phosphate binder. The investigated group of patients did not receive tetracycline, cholestyramine, or antacids.

The clinical study was divided into 3 periods. Each period has lasted for 4 weeks. In the first washout period of the study, hemodialyzed patients were treated by drugs containing neither iron nor vitamin C. In the second study period, the investigated group of patients was supplemented orally by Sorbifer Durules. The weekly dose of this drug was 7 tablets. Two tablets of Sorbifer Durules were administered after the first hemodialysis, 2 tablets after the second hemodialysis and 3 tablets after the third hemodialysis. In the third clinical study period (ie, the second washout period), hemodialyzed patients were supplemented neither by iron nor by vitamin C.

Serum iron and total iron-binding capacity were determined by spectrophotometric methods with Bio-La-Tests (PLIVA=Lachema AS, Brno, Czech Republic)17 serum ferritin was determined by chemiluminescent enzyme immunometric assay using Immulite Ferritin kit (Diagnostic Products Corp, Los Angeles, CA), serum vitamin C was determined by spectrophotometric method18 and plasma oxalic acid was determined by enzymatic spectrophotometric method with oxalate oxidase, which is free from vitamin C interference.19 Statistical analysis of obtained results was performed using commercial statistical programmes Statgraphics (Manuqistics, USA) and Arcus Quickstat Bio (A. W. Lougman, Biomedica, England). Statistic significance between investigated parameters was performed with paired-test analysis of variance (ANOVA).

Results 

The mean level of serum urea was 22.4 ± 7.1 mmol/L and serum creatinine was 795 ± 161 μmol/L in the investigated group of hemodialyzed patients during 12 weeks of the study. No influence of the drug Sorbifer Durules on these parameters was found.

The levels of hematocrit and blood hemoglobin before the beginning of the study were on the lower margin of target values during r-HuEPO treatment. During the first washout period of the study no significant change in these parameters was observed. Four-week treatment with drug containing iron and vitamin C led to the significant increase of hematocrit and blood hemoglobin values. The levels of these parameters significantly declined during the next 4 weeks without supplementation of iron and vitamin C. Concentration of serum iron was in the normal range at the beginning of the study and 4-week treatment without iron and vitamin C led to its significant decline. Four-week treatment by Sorbifer Durules significantly elevated the level of serum iron, but the next 4 weeks without iron and vitamin C treatment significantly decreased its level. Serum total iron-binding capacity was in the normal range during the whole study (Fig. 1).

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Fig. 1. Hematocrit, blood hemoglobin, serum iron and total iron − binding capacity in hemodialyzed patients.

Serum transferrin saturation was in the normal range and serum ferritin was significantly elevated during all periods of the clinical study. Serum ferritin nonsignificantly declined in the last period of the study. At the beginning of the study the mean value of serum vitamin C was on the upper margin of normal range and plasma oxalate was significantly increased. Four-week treatment without drug containing iron and vitamin C led to the significant decrease of serum vitamin C during both washout periods. Treatment by Sorbifer Durules led to the significant increase of serum vitamin C. Plasma oxalate remained unchanged during the whole clinical study (Fig. 2).

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Fig. 2. Serum transferrin saturation, ferritin, vitamin C and plasma oxalate in hemodialyzed patients.

Significant direct relationships between blood hemoglobin and serum iron (r = 0.648, P < .01) and serum transferrin saturation (r = 0.552, P < .01), between serum iron and transferrin saturation (r = 0.872, P < .001) and ferritin (r = 0.541, P < 0.01), between serum ferritin and transferrin saturation (r = 0.574, P < .01) were found. In addition, a significant direct relationship between plasma oxalate and serum creatinine (r = 0.823, P < .001) was found.

Discussion 

In this short-term clinical study, oral use of the drug containing iron and vitamin C, Sorbifer Durules, led to the increase of hematocrit, blood hemoglobin, serum iron, and vitamin C. Serum transferrin saturation was in the normal range during the whole study. At the beginning of the study, the investigated group of hemodialyzed patients was very well iron-saturated after its long-term intravenous administration in doses of 50 to 100 mg/3 times/wk. After the omission of iron treatment (first washout period), serum iron fell to a level that did not influence blood hemoglobin and hematocrit. Blood hemoglobin and hematocrit at the beginning of the study and during the first washout period were on the lower margin of target values of these parameters during r-HuEPO treatment. During the second washout period, the serum iron level significantly decreased and was near the same as during the first washout period. Consequently, it came to the decrease of blood hemoglobin and hematocrit to the levels near the same, which were found during the first washout period. The result is that the level of serum iron during the first and second washout period was adequate for maintenance of blood hemoglobin and hematocrit at the lower margin of target values during r-HuEPO treatment.

In consequence of the intravenous administration of iron before the beginning of the clinical study hyperferritinaemia developed, which nonsignificantly declined in the last period of the clinical study. At this time, hyperferritinaemia and functional iron deficiency in iron overloaded patients is treated by long-term intravenous administration of vitamin C (100-500 mg/3 times/wk). After this treatment, significant increase of blood hemoglobin, serum iron, and transferrin saturation and decrease of serum ferritin were observed.5 Intravenously administration of large dose of vitamin C has the positive and negative effect in hemodialyzed patients. Positive effect was manifested by influence on functional iron deficiency and by consequent increase of r-HuEPO effect. Negative influence was manifested by further increase of previously present hyperoxalaemia.5

The advantage of the drug used in this study was the fact that 1 tablet of Sorbifer Durules contained bivalent iron (100 mg) and vitamin C (60 mg). The application of 2 drugs in a single tablet is more suitable for hemodialyzed patients than the supplementation by 2 drugs using 2 tablets. The combination of iron and vitamin C in a single drug has another advantage (ie, after supplementation of this drug an increase of iron resorption in intestine is potentiated by vitamin C directly). In addition, vitamin C in this dose prevented its deficiency during long-term hemodialysis treatment and did not lead to the enhance of hyperoxalaemia.

The drug Sorbifer Durules has a primary influence on the level of serum iron and vitamin C. Secondary influence is applied on the increased iron resorption in intestine. The third influence of this drug is an increased blood hemoglobin formation and consequently increase of blood hematocrit during simultaneous r-HuEPO treatment. Compliance of the drug Sorbifer Durules in hemodialyzed patients was very good. Constipation occured only in 4 patients, which was not the reason for interruption of this treatment.

The drug Sorbifer Durules, which was used in the past only for the treatment of iron-deficiency anaemia, is suitable also for hemodialyzed patients treated by r-HuEPO. These results should be confirmed in the long-term clinical study.