Acta Med Scand 200: 3 15-3 19. 1976
Iron Therapy in Patients Undergoing Maintenance Hernodialysis Nils Milman From Medical Department P , Division of Nephrology, Rigshospitaler, Copenhagen, Denmark
ABSTRACT. Twelve patients in maintenance hemodialysis, receiving long-term oral iron therapy, have been treated with i.v. iron dextran, in order to evaluate the effect on the Hb level. Both Hb and hematocrit were unchanged before and after the iron dextran infusion @>0.5, p>0.7, respectively). Oral iron therapy is usually sufficient to maintain an adequate iron balance in dialysed patients and should be preferred to parenteral iron in view of the better utilization and absence of side-effects. The indication for parenteral iron should be limited to patients with impaired gastrointestinal iron absorption. Anemia is a constant and inevitable feature in patients undergoing regular hemodialysis treatment (RDT) (5, 12, 22, 23). Its pathogenesis is complex and it appears to be caused both by inadequate red cell production due to lack of erythropoietin (10, 12) and by accelerated red cell loss due to hemolysis and bleeding ( 5 , 12, 23). The appreciable blood loss in connection with dialysis makes iron supplementation necessary in order to avoid iron deficiency
tein/kg b.wt./day together with vitamin supplements. Dialysis was performed for 10 hours twice weekly using the Gambro-Lundia@artificial kidney, and the degree of uremia was constant during the study. Blood sampling was restricted to a minimum, blood transfusion avoided, and no extraordinary blood loss observed in the investigation period. None of the patients had been subjected to gastrointestinal surgery or had symptoms of malassimilation or infection. All received oral iron as ferrous fumarate, 200 mg (66 mg elemental Fez+), together with ascorbic acid, 250 mg thrice daily, during 4-16 months (mean 10) before the study. Iron dextran (Imferon@)containing 500 mg elemental Fe3+ was administered to each patient in 500 ml 0.9% saline during dialysis. Bone marrow specimens were obtained by iliac crest puncture before the iron dextran infusion and the hemosiderin iron content was assessed after staining with Prussian blue (25). Hb, hematocrit, mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), corrected reticulocyte count, serum iron, plasma total iron-binding capacity (TIBC) and plasma transferrin saturation were measured before the infusion of iron dextran and at regular intervals up to 40 days thereafter, employing the methods described in earlier papers (20, 23). In statistical analysis the Wilcoxon rank sum test was used to evaluate significance of differences.
(19, 23). It has been claimed that parenteral iron induces a rise in the H b level in dialysed patients with replete iron depots (30) and the diverging opinions concerning the efficiency of oral versus parenteral iron therapy ( 1 , 6, 18, 23) prompted the present study, with the purpose of assessing whether it is possible to achieve a further rise in H b by the administration of parenteral iron to hemodialysis patients receiving long-term oral iron treatment. MATERIAL A N D METHODS Twelve patients participated in the study (Table I). All had been on RDT for MI months (mean 21) and were on a protein-restricted diet containing an average of 0.9 g pro-
RESULTS One patient (no. 1) had no detectable marrow hemosiderin iron, while the others had normal or slightly reduced hemosiderin iron stores (Table I). None of the patients presented with evidence of iron deficiency judged by the serum iron, transferrin saturation, TIBC, MCV, and MCHC, which were all within the normal range. The iron dextran infusion was followed by a transient, moderate rise in the reticulocyte count, reaching its maximum 5-10 days after the infusion (Fig. 1 and Table 11). However, the mean H b and hematocrit values were unchanged after the infuActa Med Scand 2W
316
N. Milman
Table I. Clinical data, marrow hemosiderin, duration of hemodialysis and of oral iron therapy in patients receiving iron dextran infusion
Pat. no. 1
2 3 4 5 6 7 8 9 10
II 12
Sex
0 P P P
6 6 6 6 6 6 6 6
Age (Y.)
Dialysis before iron dextran (mo.)
50 38 38 38 32 54 32 52 23 26 42 18
20 35 9 10 12 40 41 35 15 19 11
10
sion; Hb averaged 3.9k0.9 (S.D.) mmol/l before and 3.9f0.8 mmol/l 40 days after the iron infusion (p>0.5), while the hematocrit averaged 0.19f0.04 both before and after the infusion @>0.7) (Fig. I and Table 11). The administration of iron dextran induced a significant rise in serum iron and the transferrin saturation, and the plasma iron-binding capacity was exceeded in several patients (Fig. 2). Serum iron returned to pretreatment levels within 20 days after the iron dextran infusion, while a slight, permanent increase in the transferrin saturation was observed along with a slight decrease in TIBC (Table 11). MCV and MCHC did not change significantly during the study. Analysing the individual response of the patients,
Oral iron treatment before iron dextran (mo.1
Marrow hemosiderin before iron dextran (M+) Renal disease
6 16 16 4 4 7 11 9 13 10 12 I1
0 I+ I+ I+ 2+ 2+ I+ 2+ 2+ 2+ 2+ 2+
Chronic glomerulonephritis Chronic pyelonephritis Chronic glomerulonephritis Primary oxalosis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Hereditary nephropathy Chronic glomerulonephritis Nephrosclerosis Chronic glomerulonephritis
it appeared that one (no. 1) demonstrated a pronounced reticulocytosis following the iron dextran, accompanied by a distinct rise in Hb, from 2.7 to 4.3 mmol/l, and in the hematocrit, from 0.14 to 0.19. TIBC fell from 64.4 to 53.4 pmol/l, the transferrin saturation was unchanged (from 19.9 to 21.7%) and so was serum iron (from 12.8 to 1 I .6 pmol/l), while MCV rose from 89 to 95 fl. The iron dextran infusions were generally well tolerated and not accompanied by serious adverse reactions. DISCUSSION Intravenous iron dextran has been claimed to be effective in raising the Hb level in iron-deficient dialysis patients (6, 7, 14, 18, 24) as well as in
Table 11. Hematological data (mean + S . D . ) before and after iron dextran infusion in 12 patients in maintenance hemodialysis receiving long-term oral iron therapy Days after iron dextran ~
Hb (mmol/l) Hematocrit Corrected reticulocyte count (O/OO) MCV (fl) MCHC (mmol/l) Serum iron (pmol/l) TIBC (pmoUl) Transferrin saturation (%)
0
5
10
20
30
35
40
3.950.9 0.19f0.4
3.9f0.8 0.19f0.4
3.9f0.9 0.19f0.4
3.9f0.8 0.19f0.4
3.9f0.7 0.19f0.4
3.9f0.8 0.19f0.4
3.9f0.8
14f6 98k6 20.6f0.7 18.2k6.8 52.4% 1
24f8*
24f l5**
18f8
52.3+6.4* 51.6k 10.0
20f lo** 100f4 20.5f1.3 17.3f6.7 50.8f8.7
18.1k6.5 46.1f7.3**
36.4f 15.1
103.4f 18.4*
38.5f 16.5
42.7f22.2**
Significant difference from day 0: * p
Iron Therapy in Patients Undergoing Maintenance Hernodialysis Nils Milman From Medical Department P , Division of Nephrology, Rigshospitaler, Copenhagen, Denmark
ABSTRACT. Twelve patients in maintenance hemodialysis, receiving long-term oral iron therapy, have been treated with i.v. iron dextran, in order to evaluate the effect on the Hb level. Both Hb and hematocrit were unchanged before and after the iron dextran infusion @>0.5, p>0.7, respectively). Oral iron therapy is usually sufficient to maintain an adequate iron balance in dialysed patients and should be preferred to parenteral iron in view of the better utilization and absence of side-effects. The indication for parenteral iron should be limited to patients with impaired gastrointestinal iron absorption. Anemia is a constant and inevitable feature in patients undergoing regular hemodialysis treatment (RDT) (5, 12, 22, 23). Its pathogenesis is complex and it appears to be caused both by inadequate red cell production due to lack of erythropoietin (10, 12) and by accelerated red cell loss due to hemolysis and bleeding ( 5 , 12, 23). The appreciable blood loss in connection with dialysis makes iron supplementation necessary in order to avoid iron deficiency
tein/kg b.wt./day together with vitamin supplements. Dialysis was performed for 10 hours twice weekly using the Gambro-Lundia@artificial kidney, and the degree of uremia was constant during the study. Blood sampling was restricted to a minimum, blood transfusion avoided, and no extraordinary blood loss observed in the investigation period. None of the patients had been subjected to gastrointestinal surgery or had symptoms of malassimilation or infection. All received oral iron as ferrous fumarate, 200 mg (66 mg elemental Fez+), together with ascorbic acid, 250 mg thrice daily, during 4-16 months (mean 10) before the study. Iron dextran (Imferon@)containing 500 mg elemental Fe3+ was administered to each patient in 500 ml 0.9% saline during dialysis. Bone marrow specimens were obtained by iliac crest puncture before the iron dextran infusion and the hemosiderin iron content was assessed after staining with Prussian blue (25). Hb, hematocrit, mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), corrected reticulocyte count, serum iron, plasma total iron-binding capacity (TIBC) and plasma transferrin saturation were measured before the infusion of iron dextran and at regular intervals up to 40 days thereafter, employing the methods described in earlier papers (20, 23). In statistical analysis the Wilcoxon rank sum test was used to evaluate significance of differences.
(19, 23). It has been claimed that parenteral iron induces a rise in the H b level in dialysed patients with replete iron depots (30) and the diverging opinions concerning the efficiency of oral versus parenteral iron therapy ( 1 , 6, 18, 23) prompted the present study, with the purpose of assessing whether it is possible to achieve a further rise in H b by the administration of parenteral iron to hemodialysis patients receiving long-term oral iron treatment. MATERIAL A N D METHODS Twelve patients participated in the study (Table I). All had been on RDT for MI months (mean 21) and were on a protein-restricted diet containing an average of 0.9 g pro-
RESULTS One patient (no. 1) had no detectable marrow hemosiderin iron, while the others had normal or slightly reduced hemosiderin iron stores (Table I). None of the patients presented with evidence of iron deficiency judged by the serum iron, transferrin saturation, TIBC, MCV, and MCHC, which were all within the normal range. The iron dextran infusion was followed by a transient, moderate rise in the reticulocyte count, reaching its maximum 5-10 days after the infusion (Fig. 1 and Table 11). However, the mean H b and hematocrit values were unchanged after the infuActa Med Scand 2W
316
N. Milman
Table I. Clinical data, marrow hemosiderin, duration of hemodialysis and of oral iron therapy in patients receiving iron dextran infusion
Pat. no. 1
2 3 4 5 6 7 8 9 10
II 12
Sex
0 P P P
6 6 6 6 6 6 6 6
Age (Y.)
Dialysis before iron dextran (mo.)
50 38 38 38 32 54 32 52 23 26 42 18
20 35 9 10 12 40 41 35 15 19 11
10
sion; Hb averaged 3.9k0.9 (S.D.) mmol/l before and 3.9f0.8 mmol/l 40 days after the iron infusion (p>0.5), while the hematocrit averaged 0.19f0.04 both before and after the infusion @>0.7) (Fig. I and Table 11). The administration of iron dextran induced a significant rise in serum iron and the transferrin saturation, and the plasma iron-binding capacity was exceeded in several patients (Fig. 2). Serum iron returned to pretreatment levels within 20 days after the iron dextran infusion, while a slight, permanent increase in the transferrin saturation was observed along with a slight decrease in TIBC (Table 11). MCV and MCHC did not change significantly during the study. Analysing the individual response of the patients,
Oral iron treatment before iron dextran (mo.1
Marrow hemosiderin before iron dextran (M+) Renal disease
6 16 16 4 4 7 11 9 13 10 12 I1
0 I+ I+ I+ 2+ 2+ I+ 2+ 2+ 2+ 2+ 2+
Chronic glomerulonephritis Chronic pyelonephritis Chronic glomerulonephritis Primary oxalosis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Hereditary nephropathy Chronic glomerulonephritis Nephrosclerosis Chronic glomerulonephritis
it appeared that one (no. 1) demonstrated a pronounced reticulocytosis following the iron dextran, accompanied by a distinct rise in Hb, from 2.7 to 4.3 mmol/l, and in the hematocrit, from 0.14 to 0.19. TIBC fell from 64.4 to 53.4 pmol/l, the transferrin saturation was unchanged (from 19.9 to 21.7%) and so was serum iron (from 12.8 to 1 I .6 pmol/l), while MCV rose from 89 to 95 fl. The iron dextran infusions were generally well tolerated and not accompanied by serious adverse reactions. DISCUSSION Intravenous iron dextran has been claimed to be effective in raising the Hb level in iron-deficient dialysis patients (6, 7, 14, 18, 24) as well as in
Table 11. Hematological data (mean + S . D . ) before and after iron dextran infusion in 12 patients in maintenance hemodialysis receiving long-term oral iron therapy Days after iron dextran ~
Hb (mmol/l) Hematocrit Corrected reticulocyte count (O/OO) MCV (fl) MCHC (mmol/l) Serum iron (pmol/l) TIBC (pmoUl) Transferrin saturation (%)
0
5
10
20
30
35
40
3.950.9 0.19f0.4
3.9f0.8 0.19f0.4
3.9f0.9 0.19f0.4
3.9f0.8 0.19f0.4
3.9f0.7 0.19f0.4
3.9f0.8 0.19f0.4
3.9f0.8
14f6 98k6 20.6f0.7 18.2k6.8 52.4% 1
24f8*
24f l5**
18f8
52.3+6.4* 51.6k 10.0
20f lo** 100f4 20.5f1.3 17.3f6.7 50.8f8.7
18.1k6.5 46.1f7.3**
36.4f 15.1
103.4f 18.4*
38.5f 16.5
42.7f22.2**
Significant difference from day 0: * p
