Iron supplementation in adolescent hemodialysis patients

AIMS: Iron supplementation is necessary in children on hemodialysis, but the optimal protocol remains unknown. We studied the effects of changing our unit's protocol from oral iron with periodic doses of parenteral iron dextran to routine administration of parenteral sodium ferric gluconate on anemia and iron parameters. METHODS: We followed seven hemodialysis patients aged 15 20 years (mean 17 years). Hemoglobin, hematocrit, serum iron, transferrin saturation, ferritin, erythropoietin dose, total elemental iron dose and total iron cost for the six months prior to the protocol change were compared to the same variables during the six months following the change. RESULTS: There was no statistically significant difference between the doses of parenteral iron between the two protocols; however, the total dose of elemental iron administered in the oral iron plus iron dextran protocol was greater than in the sodium ferric gluconate protocol (19.6+/-13.1 (mean+/-SD) mg/kg/week versus 1.1+/-0.3 mg/kg/week; p = 0.03). Both protocols had equivalent efficacy with respect to hemoglobin, ferritin and other measures of iron stores. On the other hand, the costs of sodium ferric gluconate were significantly higher than those of oral iron plus intermittent iron dextran (157.75+/-45.94 $/patient/month versus 52.08+/-49.88 $/patient/month; p = 0.01). CONCLUSIONS: Routine administration of sodium ferric gluconate is equivalent if not superior to use of oral iron plus iron dextran for maintenance of iron stores in adolescents on hemodialysis, but more expensive.     

Intravenous iron supplementation for the treatment of anaemia in pre-dialyzed chronic renal failure patients.

BACKGROUND: Intravenous iron is a recognized therapy of anaemia in chronic haemodialyzed patients, especially in those receiving erythropoietin (Epo), while its role in the anaemia of pre-dialyzed chronic renal failure (CRF) patients is much less clear. This study attempted to evaluate the effects of intravenous iron in anaemic pre-dialyzed patients. METHODS: Sixty anaemic (haemoglobin<11 g/dl) non-diabetic patients with moderate CRF [32 males, 28 females; mean age 52.2+/-12.5 years; mean glomerular filtration rate 36.2+/-5.2 ml/min], without iron deficiency, iron overload or inflammation, without concomitant erythropoietin treatment and without any previous iron therapy were enrolled. Intravenous iron was administered as iron sucrose, 200 mg elemental iron per month for 12 months, with 1 month pre-study survey and 1 month follow-up after the last iron dose. RESULTS: Intravenous iron supplementation was associated with a significant increase in haemoglobin (from 9.7+/-1.1 at the baseline to 11.3+/-2.5 g/dl after 12 months, a mean increase of 1.6 g/dl), a further 36% of patients reaching the target haemoglobin of 10 g/dl. There was a significant increase in serum iron from 73.9+/-17.2 to 101.8+/-12.2 microg/dl, in serum ferritin from 98.0 (24.8-139.0) to 442.5 (86.0-496.0) microg/l and in transferrin saturation from 21.6+/-2.6 to 33.6+/-3.2%. No worsening of renal function, no increase in blood pressure and no other side effects were noted. CONCLUSIONS: Intravenous iron therapy in pre-dialysis patients with no Epo seems often to ameliorate the anaemia, avoiding the necessity of Epo or blood transfusions in one-third of pre-dialyzed non-diabetic patients. Intravenous iron supplementation appears to be an effective and safe treatment for anaemia in pre-dialysis CRF patients.     

Iron status in patients receiving erythropoietin for dialysis-associated anemia

Adequate body iron stores are crucial to assuring rapid and complete response to recombinant human erythropoietin (rHuEPO). In the present study, markers of iron storage were examined in 27 patients with normochromic, normocytic anemia undergoing acute rHuEPO (150 to 300 U/kg t.i.w.) treatment for anemia. We calculated projected iron needed for new hemoglobin synthesis from the difference between initial and target hemoglobin concentrations, initial iron reserves available from initial serum ferritin levels, and net projected surplus or deficit from the difference between needs and reserves. Of 22 patients predicted to develop iron deficiency (mean projected deficit 268 +/- 70 mg), 20 developed evidence of exhausted iron stores (transferrin %sat less than 16 or ferritin less than 30 micrograms/liter) before reaching target hemoglobin; two predicted to become deficient (projected deficit less than 100 mg) did not; and all five predicted to avoid iron deficiency (mean projected surplus 177 +/- 20 mg) remained iron replete. During acute rHuEPO therapy net body iron balance remained neutral in patients receiving no iron supplements and increased 5 mg/kg in patients prescribed oral ferrous sulfate. However, in patients given iron dextran i.v. less than 60% of elemental iron administered became measurable as iron stores or usable for hemoglobin synthesis.     

Efficacy and safety of oral versus intravenous ascorbic acid for anaemia in haemodialysis patients

BACKGROUND: Intravenous (i.v.) ascorbic acid (AA) improves anaemia in iron-overloaded, erythropoietin (rEPO) hyporesponsive haemodialysis patients. While oral AA is readily attainable, the efficacy and safety of oral versus i.v. AA has not been examined. METHODS: We conducted an open-label randomised parallel study on the effects of 8 weeks of 250 mg oral AA (n=10) compared with 250 mg i.v. AA (n=11) 3x/week on haemoglobin (Hb), ferritin and rEPO dose in 21 iron-overloaded haemodialysis patients. We also examined the effect of 3 months of 500 mg oral AA 3x/week (n=70) compared with no treatment (n=83) on Hb, ferritin and rEPO dose in 153 haemodialysis patients. RESULTS: Patients had severe AA deficiency (mean 2.2+/-SE 0.4 mg/L; normal range, 4.0-14.0). Following treatment, the plasma AA level increased (P<0.001), but was not significantly different between the groups. There was no change in Hb, iron availability and rEPO dose with oral or i.v. AA. There was a significant increase in serum oxalate but no significant changes in left ventricular function or renal calculi formation. In the second study, oral AA had no effect on Hb, rEPO dose and ferritin in the whole group and a subgroup of 30 with anaemia. CONCLUSION: Haemoglobin and iron availability did not improve following oral or i.v. AA in this select small group of iron-overloaded haemodialysis patients or in a larger population of haemodialysis patients given oral AA at a higher dose and for a longer duration. AA supplementation may still be warranted in view of severe AA deficiency in haemodialysis patients.     

Role of type of vascular access in erythropoietin and intravenous iron requirements in haemodialysis.

BACKGROUND: Recent data have suggested the existence of a relationship between the use of synthetic vascular accesses and increased erythropoietin (Epo) requirements. The present study aimed to evaluate the possible role of the type of vascular access in both Epo and intravenous (i.v.) iron requirements. METHODS: One-hundred-and-seven individuals without recognized causes of Epo resistance, 62 of them undergoing chronic haemodialysis through native arteriovenous fistulae (AVF) and 45 through PTFE grafts, were retrospectively studied (one-year follow-up). Sixty-nine patients, i.e. all but three with a PTFE graft and 27 with native AVF, were taking anti-platelet agents. Doses of i.v. iron and Epo and laboratory parameters were recorded. RESULTS: Erythropoietin and i.v. iron requirements were higher in the patients dialysed through PTFE grafts compared with those with native AVF (Epo: 103.8+/-58.4 vs 81.0+/-44.5 U/kg/week, P=0.025; i.v. iron: 178.9+/-111 vs. 125.9+/-96 mg/month, P=0.01). On a yearly basis, the difference in Epo dose represented a total of 94582+/-16789 U Epo/patient/year. Moreover, the patients with PTFE grafts received more red blood cell transfusions than patients with native AVF (P=0.021). No differences between laboratory, dialysis kinetics, demographic or comorbidity parameters were found. The type of vascular access was the best predictor of the requirement of > or =150 U/kg/week Epo (P=0.03). Even though the patients who received anti-platelet therapy required more i.v. iron (167.5+/-103.6 vs. 114.5+/-101.4 mg/month, P=0.008) but not more Epo (P=NS), the possibility of an accessory role of anti-platelet agents in the increased Epo requirements with PTFE grafts cannot be ruled out. CONCLUSIONS: The use of a PTFE graft and anti-platelet drugs represents a previously undescribed association related to higher Epo and i.v. iron requirements. The association described herein adds new arguments to the debate concerning the choice of vascular access in chronic haemodialysis patients.     

Ascorbic acid does not augment the restoration effect of iron treatment for empty iron stores in patients after gastrointestinal surgery

The effect of a 6-week combined treatment with ferrous sulfate (80 mg Fe++ three times daily) and ascorbic acid (75 mg three times daily) on the empty iron stores in 20 patients after gastrointestinal surgery was examined from changes of serum ferritin. One group of 20 patients with similar clinical characteristics served as controls. The treatment replaced the empty iron stores. Since mean serum ferritin concentrations increased from 9 +/- 8 to 29 +/- 11 micrograms/l (P less than 0.001) in males and from 8 +/- 8 to 26 +/- 10 micrograms/l (P less than 0.001) in the females. Also blood hemoglobin and serum iron concentrations increased significantly (P less than 0.01). Among the controls there were no marked changes in serum ferritin, blood hemoglobin or serum iron concentrations. However, the increase of serum ferritin caused by this combined treatment was similar with that caused previously by pure ferrous sulfate treatment. Thus, it is considered that the combined treatment with ferrous sulfate (80 mg Fe++ three times daily) and ascorbic acid (75 mg three times daily) restores the empty iron stores in patients after gastrointestinal surgery, but that the increase is not augmented by the ascorbic acid. Thus, a pure iron therapy is recommended to fill up the empty iron stores in these patients.     

A randomized controlled trial of oral versus intravenous iron in chronic kidney disease

BACKGROUND: It is unknown whether intravenous iron or oral iron repletion alone can correct anemia associated with chronic kidney disease (CKD). We conducted a randomized multicenter controlled trial in adult anemic, iron-deficient non-dialysis CKD (ND-CKD) patients (>or=stage 3) not receiving erythropoiesis-stimulating agents (ESAs). METHODS: The participants were randomized to receive either a sodium ferric gluconate complex (intravenous iron) 250 mg i.v. weekly x 4 or ferrous sulfate (oral iron) 325 mg t.i.d. x 42 days. Hemoglobin (Hgb), ferritin and transferrin saturation (TSAT) were measured serially, and the Kidney Disease Quality of Life (KDQoL) questionnaire was administered on days 1 and 43. The primary outcome variable was change from baseline (CFB) to endpoint in Hgb values. RESULTS: Seventy-five patients were analyzed (intravenous iron n = 36, oral iron n = 39). CFB in Hgb was similar in the two groups (intravenous iron 0.4 g/dl vs. oral iron 0.2 g/dl, p = n.s.). However, the increase in Hgb was only significant with intravenous iron (p < 0.01). In comparison to oral iron, intravenous iron achieved greater improvements in ferritin (232.0 +/- 160.8 vs. 55.9 +/- 236.2 ng/ml, p < 0.001) and TSAT (8.3 +/- 7.5 vs. 2.9 +/- 8.8%, p = 0.007). Intravenous iron caused greater improvements in KDQoL scores than oral iron (p < 0.05). The most common side effect reported with intravenous iron was hypotension, while constipation was more common with oral iron. CONCLUSIONS: Oral and intravenous iron similarly increase Hgb in anemic iron-depleted ND-CKD patients not receiving ESAs. Although in comparison to oral iron, intravenous iron may result in a more rapid repletion of iron stores and greater improvement in quality of life, it exposes the patients to a greater risk of adverse effects and increases inconvenience and cost.     

Efficacy prospective study of different frequencies of Epo administration by i.v. and s.c. routes in renal replacement therapy patients.

BACKGROUND: The problem of pure red cell aplasia (PRCA) prompted nephrologists to revert to a wider intravenous (i.v.) utilization of erythropoeitin (Epo). Once weekly i.v. Epo administration has been suggested to be as effective as the twice/thrice weekly i.v. dose. The aim of the present study was to test whether once weekly i.v. Epo administration is equally as cost-effective as once weekly subcutaneous (s.c.) and 2-3 times weekly i.v. administration. METHODS: We prospectively studied 41 patients (23 males, aged 28-82 years), on renal replacement therapy for 18-286 months, stabilized on twice or thrice weekly s.c. Epo-alpha (basal). The patients were treated for three consecutive 6 month periods with once weekly s.c. (OWSC), once weekly i.v. (OWIV) and twice/thrice weekly i.v. (TWIV) Epo-alpha. The initial dose for each period was equal to the final dose of the previous one; when necessary, the dose was adjusted according to DOQY guidelines. Iron, folic acid and vitamin B(12) supplementations were given throughout all the study periods. At the end of each of the four study periods, the following parameters were evaluated: haemoglobin, haematocrit, hypochromic red blood cells (RBCs), iron, serum ferritin, transferrin, folate, vitamin B(12), C-reactive protein (CRP), Kt/V, parathyroid hormone (PTH) and weekly dose of Epo-alpha. RESULTS: Thirty-three out of 41 enrolled patients completed the study (there were five deaths, two renal transplants and one transfer). No significant changes were observed as regards iron, serum ferritin, transferrin, folate, vitamin B(12), CRP, Kt/V or PTH level. Haemoglobin levels were not different at the end of the basal (11.7+/-1.21), OWSC (11.8+/-0.86) and TWIV (12.1+/-1.04) periods, while significantly lower levels were observed after the OWIV period (11.0+/-0.97, P<0.01). Weekly Epo consumption (Epo U/week/kg body weight/g haemoglobin) was: basal 11.57+/-5.96; OWSC 10.22+/-4.53; OWIV 15.99+/-7.7*(a); and TWIV 11.89+/-6.3*(a) (*P<0.01 vs basal; (a)P<0.01 vs OWSC). CONCLUSIONS: From our results, the OWIV schedule seems to have less efficacy in the control of anaemia of chronic renal failure patients on dialysis treatment than either OWSC or TWIV schedules.     

Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin

We assessed the efficacy of intravenous (i.v.) iron saccharate (VENOFER) vs oral iron supplementation in haemodialysis patients treated with low-dose erythropoietin (EPO). Twenty haemodialysis patients with serum ferritin >200 ng/mL and transferrin saturation >30% were assigned to one of the two groups. In Group 1, 10 were given i.v. iron saccharate (100 mg i.v. twice weekly) post dialysis. In Group 2, oral ferrous sulphate 200 mg was given thrice daily. In both groups, subcutaneous EPO 25 units/kg body weight (BW) was started simultaneously, twice weekly. After 3 months (study completion) the mean haemoglobin and haematocrit was significantly increased in Group 1 than in Group 2 (Hb 11.60±0.64 G/dL vs 10.5 G/dL±1.14 P <0.01). The final mean EPO dose was 25% lower in Group 1 than in Group 2 (3400±1356 U/week vs 4600±1356 U/week P =0.10) and the mean serum ferritin was higher in the i.v. iron group than the oral group (671 ng/mL±388 vs 367 ng/mL±238 P =NS). The same was also observed with transferrin saturation (44.6%±19.8 in Group 1 vs. 29%±11.0 in Group 2 P =NS). No adverse effects were seen during the study. In conclusion, we observed that regular use of i.v. iron had a significantly enhanced haemoglobin response, better maintained serum ferritin and lower EPO dosage requirement than the oral iron group.     

Increase of body iron stores estimated by the increase of serum ferritin concentration during a treatment of 200 mg Fe++ daily after gastrointestinal surgery

A 6-week iron therapy of 200 mg Fe++ daily was given to 13 men and 12 women who had previously undergone various kinds of common gastrointestinal surgery and who had empty iron stores estimated from low serum ferritin concentration. The results were compared with those of a control group corresponding to the study group in respect of sex, number of patients, primary disease, previous operation, empty iron stores (serum ferritin), blood hemoglobin, serum iron, sedimentation rate, blood leukocytes, serum transferrin, folate and vitamin B12. The iron therapy restored the lack of body iron, for the serum ferritin concentrations increased from 12 +/- 7 to 30 +/- 11 micrograms/l (p less than 0.001) in the men and from 10 +/- 6 to 30 +/- 12 micrograms/l (p less than 0.001) in the women, whereas the corresponding changes in the control group were from 10 +/- 9 to 11 +/- 8 micrograms/l and from 11 +/- 8 to 13 +/- 11 micrograms/l in the men and women, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Issues related to iron replacement in dialyzed patients

Correction of renal anaemia by erythropoiesis stimulating agents (ESA) had reduced blood transfusion needs and iron overload risk and nowadays most of end-stage renal disease patients treated with dialysis requires i.v. iron supplementation to optimize the action of ESAs. Recommended targets for iron therapy are serum ferritin > 100 microg/l and hypochromic red cells percentage (HRC) < 10 (or transferrin saturation coefficient [TSAT] > 20% or reticulocyte Hb content [CHr] > 29 pg/cell). If i.v. administration is strongly recommended for all dialysis patients, controversies remain for the mode and rhythm of administration. Follow-up should be done every 1 to 3 months with measurement of serum ferritin in order to keep its level < 500 to 800 microg/l. Potential toxicity of chronic exposure to i.v. iron concerns tissue accumulation, consequences of pro-oxidant effects, cardiovascular damage and increased risk of infection but no clinical data unequivocally confirm that iron overload from parenteral iron contributes to all cause morbidity and mortality. In conclusion, i.v. iron should be used to optimize ESA action and could be used safety if dosage is < or = 100 mg/week and serum ferritin < 500 a 800 microg/l.     

Ranitidine bioavailability and disposition kinetics in patients undergoing chronic hemodialysis

The absorption and disposition of single-dose intravenous (i.v.) and oral ranitidine were evaluated in 6 patients undergoing chronic hemodialysis. Ranitidine was given as either 50 mg (0.16 mM) i.v. or 150 mg (0.48 mM) tablets 4 h prior to hemodialysis according to a randomized cross-over design with tests separated by 2 weeks. Following i.v. administration, the peak serum ranitidine concentration was 761 +/- 207 micrograms/l (mean +/- SD) and the observed peak after the oral dose was 833 +/- 206 micrograms/l at 3.5 +/- 1.2 h. To convert micrograms/l to microM/l, divide by 314. The terminal elimination rate constants for the i.v. and oral doses were 0.062 +/- 0.013 and 0.058 +/- 0.004 h-1, respectively, with an apparent volume of distribution of 139.6 +/- 35.3 liters and total body clearance 8.5 +/- 1.6 liters/h for the i.v. dose. Hemodialysis clearances during the i.v. and oral studies were 3.2 +/- 0.9 and 3.1 +/- 1.0 liters/h, respectively, and the mean amount removed by hemodialysis following i.v. administration was 3.9 +/- 2.7 mg. The bioavailability of ranitidine was 54.3 +/- 13.5%. Based on these single-dose data, a daily oral dose of 150 mg ranitidine in patients with end-stage renal disease should provide a mean ranitidine serum concentration of approximately 350 micrograms/l with less than 10% of body stores of ranitidine being lost during any dialysis session.     

Melatonin corrects reticuloendothelial blockade and iron status in haemodialysed patients

AIM: Treatment of anaemia in haemodialysed patients in the setting of inflammation usually displays high levels of serum ferritin (>800 ng/mL) and low transferrin saturation (TSAT) (<20%) despite i.v. iron supplementation, thus proving iron trapping in the reticuloendothelial system. Melatonin has been reported to reduce cytokine production and, in dialysis patients, to prevent oxidative stress resulting from iron and erythropoietin treatment. METHOD: In this study, we evaluated a group of 10 patients undergoing haemodialysis who displayed elevated serum ferritin (981 +/- 44.6 ng/mL) and TSAT <20% (15.6 +/- 3.8%) after having received 1.2 g of i.v. iron dextran over a period of 8 weeks. These patients received oral melatonin, 6 mg/day at night for 30 days. RESULTS: After this treatment, all of them markedly increased TSAT values, reaching 35.5 +/- 6.7% (P < 0.0001 vs basal values). In addition, ferritin values decreased to 754.4 +/- 263.7 ng/mL (P < 0.05), and serum iron dramatically increased in all of the patients under study (42.4 +/- 9.4 vs 109.7 +/- 24.3 microg/dL; P < 0.0001). Values for haematocrit (28.6 +/- 2.7 vs 31.9 +/- 3.57%; P < 0.05) and haemoglobin (9.19 +/- 0.97 vs 10.04 +/- 1.29 g/dL; P < 0.05) were also improved. Measurements were then repeated 2 weeks after melatonin withdrawal, showing an impressive decrease in TSAT (16.4 +/- 5.3%; P < 0.00001) and serum iron (48 +/- 14.7 microg/dL; P < 0.0001) values and an almost significant increase in ferritin values (954.4 +/- 86 ng/mL; P < 0.054). CONCLUSION: The present study demonstrates that melatonin may strongly correct the reticuloendothelial blockade seen in dialysis patients under an inflammatory status, thus allowing a better management of iron derangements and renal anaemia.     

Effect of repeated intravenous iron administration in haemodialysis patients on serum 8-hydroxy-2'-deoxyguanosine levels.

BACKGROUND: Iron supplementation is a mainstay for management of renal anaemia in patients receiving haemodialysis (HD). Although it is well known that a single intravenous iron (IVIR) administration transiently enhances oxidative stress in HD patients, the consequence of repeated IVIR administration is still unknown. This study aims to clarify the time course of changes in serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, during a period of repeated IVIR administration in HD patients. METHODS: Twenty-seven patients (62+/-14 years and 23 males) on long-term HD participated in this study. All patients had been on HD more than 6 months and none had received a blood transfusion or iron therapy in previous 6 months. The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels as a marker of body iron stores: IVIR group (Ht<30% and FTN<100 ng/ml; n=7); High FTN group (Ht>or=30% and FTN>or=100 ng/ml; n=11); and low FTN group (Ht>or=30% and FTN<100 ng/ml; n=9). The IVIR group patients received 40 mg of ferric saccharate i.v. after each HD session until Ht increased by 5%. Serum 8-OHdG and other parameters were prospectively monitored for 10 weeks. RESULTS: At baseline, the serum ferritin level was independently associated with 8-OHdG in a multiple regression model (total adjusted R2=0.47, P<0.01). All patients in the IVIR group achieved the target Ht level during the study. IVIR administration resulted in significant increases in 8-OHdG levels (0.22+/-0.07-0.50+/-0.16 ng/ml: baseline to 10 week) as compared with both the high FTN group (0.52+/-0.20-0.58+/-0.28 ng/ml) and the low FTN group (0.39+/-0.11-0.36+/-0.11 ng/ml) (ANOVA for repeated measures P<0.01). Additionally, serum 8-OHdG and serum ferritin changed in the same manner. CONCLUSIONS: Repeated IVIR administration for HD patients was associated with signs of increased oxidative DNA injury, as reflected by increased serum levels of 8-OHdG. As these changes were accompanied by increased serum ferritin levels, excess body iron stores might play an important role in oxidative stress.     

Iron supplementation in haemodialysis - practical clinical guidelines

Background. The aim of this prospective study was to test a new protocol for iron supplementation in haemodialysis patients, as well as to assess the utility of different iron metabolism markers in common use and their 'target' values for the correction of iron deficiency. Methods. Thirty-three of 56 chronic haemodialysis patients were selected for long-term (6 months) i.v. iron therapy at 20 mg three times per week post-dialysis based on the presence of at least one of the following iron metabolism markers: percentage of transferrin saturation (%TSAT) <20%; percentage of hypochromic erythrocytes (%HypoE) >10% and serum ferritin (SF) <400 &mgr;g/l. Reasons for patient exclusion were active inflammatory or infectious diseases, haematological diseases, psychosis, probable iron overload (SF ⩾400 &mgr;g/l) and/or acute need of blood transfusion mostly due to haemorrhage and change in renal replacement treatment. Results. More than half (51.8%) of the patients of our dialysis centre proved to have some degree of iron deficiency in spite of their regular oral iron supplementation. At the start of the study the mean haemoglobin was 10.8 g/dl and increased after the 6 months of iron treatment to 12.8 g/dl (P<0.0001). The use of erythropoietin decreased from 188 units/kg/week to 84 units/kg/week. The criterion for iron supplementation with the best sensitivity/specificity relationship (100/87.9%) was ferritin <400 &mgr;g/l. Patients with ferritin <100 &mgr;g/l and those with ferritin between 100 &mgr;g/l and 400 &mgr;g/l had the same increase in haemoglobin but other parameters of iron metabolism were different between the two groups. Conclusions. Routine supplementation of iron in haemodialysis patients should be performed intravenously. Target ferritin values should be considered individually and the best mean haemoglobin values were achieved at 6 months with a mean ferritin of 456 &mgr;g/l (variation from to 919 &mgr;g/l). The percentage of transferrin saturation, percentage of hypochromic erythrocytes and ferritin <100 &mgr;/l, were not considered useful parameters to monitor routine iron supplementation in haemodialysis patients. No significant adverse reactions to iron therapy were observed. Keywords: erythropoietin; ferritin; haemodialysis; iron; intravenous      

Experience of iron saccharate supplementation in haemodialysis patients treated with erythropoietin

SUMMARY: We assessed the efficacy of intravenous (i.v.) iron saccharate (VENOFER) vs oral iron supplementation in haemodialysis patients treated with low-dose erythropoietin (EPO). Twenty haemodialysis patients with serum ferritin >200 ng/mL and transferrin saturation >30% were assigned to one of the two groups. In Group 1, 10 were given i.v. iron saccharate (100 mg i.v. twice weekly) post dialysis. In Group 2, oral ferrous sulphate 200 mg was given thrice daily. In both groups, subcutaneous EPO 25 units/kg body weight (BW) was started simultaneously, twice weekly. After 3 months (study completion) the mean haemoglobin and haematocrit was significantly increased in Group 1 than in Group 2 (Hb 11.60 ± 0.64 G/ dL vs 10.5 G/dL ± 1.14 P <0.01). the final mean EPO dose was 25% lower in Group 1 than in Group 2 (3400 ± 1356 U/week vs 4600 ± 1356 U/week P =0.10) and the mean serum ferritin was higher in the i.v. iron group than the oral group (671 ng/mL ± 388 vs 367 ng/mL ± 238 P =NS). the same was also observed with transferrin saturation (44.6%± 19.8 in Group 1 vs. 29%± 11.0 in Group 2 P =NS). No adverse effects were seen during the study. In conclusion, we observed that regular use of i.v. iron had a significantly enhanced haemoglobin response, better maintained serum ferritin and lower EPO dosage requirement than the oral iron group.     

Percentage of hypochromic red blood cells as predictor of erythropoietic and iron response after i.v. iron supplementation in maintenance haemodialysis patients

Background. The percentage of hypochromic red blood cells (RBC), defined as those with a cellular haemoglobin <28 g/dl has been suggested to be a sensitive marker of functional iron deficiency in maintenance haemodialysis (HD) patients. Thus, during rHuEpo therapy an increase in hypochromic RBC to >10% would indicate that more intensive iron supplementation may be required. Methods. We investigated 70 HD patients 57.1±15.3 years old and on maintenance HD for 66.3±47.9 months without blood loss from gastrointestinal bleeding or from the vascular access, without surgery and without infectious disease or malignancy. During the study period of 12 weeks, each patient received an i.v. dose of 800 mg ferrogluconate. Haemoglobin, haematocrit, and the percentage of hypochromic RBC were measured before and every 4 weeks after the start of the study; serum ferritin, zinc protoporphyrin (ZPP) and C-reactive protein (CRP) were measured at the beginning (baseline) and end of the study. Results. At baseline the percentage of hypochromic RBC was ⩽5.0% in 28 patients, >5.0 and ⩽10.0% in 25 patients and >10.0% in 17 patients, suggesting functional iron deficiency in at least 42 patients, suggesting functional iron deficiency in at least 42 patients. Nine patients had serum ferritin values <100 &mgr;g/l; nonetheless in these patients the median percentage of hypochromic RBC was 5.9% (range 0.9-14.3%), indicating that an absolute iron deficiency can occur in the presence of normal amounts of hypochromic RBC. There was a significant correlation between serum ferritin levels and hypochromic RBC at the end, but not at the beginning, of the study. However, there was no correlation between ZPP and hypochromic RBC at any time during the study. During i.v. iron supplementation the rHuEpo dose could be reduced by 8.5% in patients with hypochromic RBC ⩽5.0%, by 11.3% in patients with hypochromic RBC>5.0 and ⩽10.0% and by 23.4% in patients with hypochromic RBC>10.0%, demonstrating the benefit of i.v. iron in patients with functional iron deficiency. In HD patients in whom serum ferritin levels remained below 290 &mgr;g/l until the end of the study, a significant reduction of the rHuEpo dosage could be obtained during i.v. iron therapy. This was not the case in patients with serum ferritin >290 &mgr;g/l after iron supplementation. We found that the percentage of hypochromic RBC is the most sensitive parameter for predicting hyporesponsiveness in CPR-positive patients. Finally our data indicate that HD patients with hypochromic RBC>6% and low to moderate increases in serum ferritin levels after i.v. iron supplementation significantly benefit from i.v. iron therapy. Conclusions. Two different aspectsshould be taken into consideration in HD patients treated with rHuEpo and concomitant i.v. iron therapy: (1) response of the erythropoietic system to rHuEpo, and (2) adequate delivery of the supplemented iron to the erythropoietic system. The patient's percentage of hypochromic RBC and increase in serum ferritin after i.v. iron supplementation should be used to decide whether or no i.v. iron should be given and to monitor this type of therapy in HD patients.     

Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis

BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.     

Intravenous iron for CAPD populations: proactive or reactive strategies?

BACKGROUND: The European best practice guideline [Nephrol Dial Transplant 1999; 14 (Suppl 5)] (5A) for the management of anaemia suggests that > 85% of the CAPD population should have a haemoglobin level of > 11.0 g/dl. METHODS: We developed and implemented an outpatient-based protocol for intravenous iron sucrose (IV Fe) and erythropoietin (Epo) in CAPD patients showing iron deficiency despite oral iron therapy. We managed a total of 103 patients over 13 months of study. All CAPD patients were included, regardless of co-morbidity. Treatment developed in two phases: in phase 1 (reactive) (months 1-8), patients with markers of iron deficiency (ferritin < 100 ng/ml or ferritin 100-500 and percentage hypochromic red cells (%HRC) > or =5) were converted from oral iron to IV Fe (300 mg) and reviewed after 4-8 weeks according to haemoglobin (Hb). In phase 2 (proactive) (months 9-13), the criteria for iron therapy were extended: ferritin < 150 ng/ml or ferritin 150-500 and %HRC > or = 2. Patients then received IV Fe (200 mg) and were reviewed after 4 weeks according to Hb. RESULTS: The median haemoglobin increased from 11.0 (Inter quartile range, IQR, 10.1-12.6) g/dl to 11.7 (11.0-12.7) g/dl (P = 0.06). The proportion of patients with absolute iron deficiency (ferritin < 100 ng/ml) decreased from 24 to 2%. The percentage of hypochromic red cells (%HRC) decreased from 4 (2-7) to 1 (1-4) (P < 0.01). CONCLUSIONS:An integrated Epo and IV Fe policy increased the number of patients reaching the European guideline from 50 to 75% with no increase in the population median Epo requirements (42 (IQR, 25-95) IU/kg/week vs 45 (27-101) (P = NS)). This study demonstrates the benefit of early (proactive) intervention in achieving population compliance within current guidelines for renal anaemia.     

Regular low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients

BACKGROUND.: Erythropoietin (Epo) is an effective but expensive treatmentfor anaemia in patients with chronic renal failure. Hyporesponsivenessto Epo, particularly in haemodialysis patients, is most commonlydue to a functional iron deficiency, which is difficult to monitorreliably. METHODS.: Forty-six stable haemodialysis patients, receiving Epo therapy,were commenced on regular low-dose intravenous iron (sodiumferric gluconate complex) at a dose of 62.5 mg/5 ml given asa slow injection post-dialysis twice weekly, weekly, or fort-nightly,according to their serum ferritin levels. Haemoglobin, serumferritin, Epo dose, and iron dose were measured at 6-weeklyintervals over a 6-month period. RESULTS: At the beginning of the study, 12 patients in the group hadferritin levels of less than 100 µg/l, and were thus consideredto potentially have an absolute iron deficiency. The study groupwas therefore split into two subgroups for the purpose of analysis,i.e. the 12 patients with ferritin levels of less than 100 µg/lat the start of the study or ‘low ferritin group’,and the remaining 34 patients with ferritin levels of greaterthan 100 µg/l at the start of the study or ‘normalferritin group’. In the low ferritin group (n=12), intravenous iron therapy increasedserum ferritin levels, and produced a significant rise in haemoglobin,and a significant reduction in Epo dose. (Ferritin pre-iron,median (range) 68 (20–96)µg/l; post-iron, 210.5(91–447)µg/l, P<0.003, Wilcoxon. Haemoglobinpre-iron, 10.05 (8.2–11.9)g/dl; post-iron, 11.0 (9.9–11.9)g/dl,P<0.03. Epo dose pre-iron, 9000 (4000–30000) i.u./week;post-iron, 6000 (2000–10000)i.u./week, P<0.05.) Similar results were obtained in the normal ferritin group (n=34)following intravenous iron therapy, with significant increasesin serum ferntin levels and haemoglobin concentrations, anda significant reduction in Epo dose. (Ferritin pre-iron, 176(103–519) µg/l; post-iron, 304.5 (121–792)µg/l,P<0.0001. Haemoglobin pre-iron, 9.85 (6.5–12.8)g/dl;post-iron: 11.25 (9.9–13.3)g/dl, P<0.0001. Epo dosepre-iron, 6000 (2000–15 000)i.u./week; post-iron, 4000(0–15000)i.u./week, P<0.005.) CONCLUSION.: Regular intravenous iron supplementation in haemodialysis patientsimproves the response to Epo therapy.