A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload

Background: Functional iron deficiency may develop and cause erythropoietin resistance in haemodialysis patients with iron overload. Controversy remains as to whether intravenous iron medication can improve this hyporesponsiveness due to decreased iron availability, or whether iron therapy will aggravate haemosiderosis. Intravenous administration of ascorbic acid has been shown to effectively circumvent resistant anaemia associated with iron overload in a small preliminary study. To elucidate further the possible mechanisms of this resistance, a parallel, comparative study was conducted to compare the effects of intravenous iron and ascorbate therapies in iron-overloaded haemodialysis patients. Methods: Fifty haemodialysis patients with serum ferritin of >500 &mgr;g/l were randomly divided into two protocols. They were further stratified into controls (Control I, n=11) and intravenous iron group (IVFE, n=15) in protocol I; and into controls (Control II, n=12) and intravenous ascorbic acid group (IVAA, n=12) in protocol II. Controls had a haematocrit of >30% and did not receive any adjuvant therapy. IVFE and IVAA patients were hyporesponsive to erythropoietin and functionally iron deficient. Ferric saccharate (100 mg dose) was administered intravenously post-dialysis on five consecutive dialysis sessions in the first 2 weeks; and ascorbic acid (300 mg dose) thrice a week for 8 weeks. Red cell and iron metabolism indices were examined before and following therapy. Results: Mean values of haematocrit and transferrin saturation were significantly lower, and erythropoietin dose was higher in IVFE and IVAA patients compared to controls. Intravenous iron therapy neither improved erythropoiesis nor reduced erythropoietin dose during 12 weeks. Iron metabolism indices significantly increased at 2 and 6 weeks, but decreased at 12 weeks returning to the baselines. In contrast, mean haematocrit significantly increased from 25.8±0.5 to 30.6±0.6% with a concomitant reduction of 20% in erythropoietin dose after 8 weeks of ascorbate therapy. Serum ferritin modestly fell but with no statistical significance. The enhanced erythropoiesis paralleled a rise in transferrin saturation from 27±3 to 48±6% and serum iron from 70±11 to 107±19 &mgr;g/dl (P<0.05). Conclusions: Short term intravenous iron therapy cannot resolve the issue of functional iron deficiency in haemodialysis patients with iron overload. Intravenous administration of ascorbic acid not only facilitates iron release from storage sites, but also increases iron utilization in the erythron. Our study draws attention to a potential adjuvant therapy, intravenous ascorbic acid, to treat erythropoietin-hyporesponsive anaemia in iron-overloaded patients.     

High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients

Background: The resistence to recombinant human erythropoietin (rHuEpo) therapy in haemodialysis (HD) patients has multifactorial aetiologies; erythropoietin insufficiency, dialysis insufficiency, iron deficiency, and secondary hyperparathyroidism. Angiotensin-converting enzyme (ACE) inhibitors induce anaemia in patients with essential hypertension, congestive heart failure, chronic renal insufficiency, and renal transplants. Data exist suggesting that ACE inhibitors impair erythropoiesis in HD patients. Therefore the aim of this study was to investigate the impact of enalapril on rHuEpo requirement. Methods: In the present prospective non-randomized study of 12 months, we compared the effects of enalapril and nifedipine on rHuEpo requirement in 40 hypertensive patients receiving rHuEpo for more than 6 months on maintenance haemodialysis. Twenty normotensive rHuEpo-dependent patients served as a control group. All patients with severe hyperparathyroidism or iron deficiency were excluded. The mean (±SD) haemoglobin concentration was >10 g/dl in all groups. The mean weekly rHuEpo dose increased in the enalapril group (P<0.0001 vs before) and remained constant in the nifedipine and control groups (P=NS vs before). Statistically, there was no differences with regard to iPTH levels, dialysis parameters, iron status, and underlying renal diseases among all groups. Conclusion: High-dose enalapril increases rHuEpo requirement and should be reserved for dialysis patients with hypertension uncontrollable with other antihypertensive medications or dialysis patients with cardiac failure.     

Lipid and apolipoprotein patterns during erythropoietin therapy: roles of erythropoietin, route of administration, and diet

Background. Long term effects of rHuEpo on the blood lipid profile have not been well documented. The aim of this paper is to prospectively evaluate whether rHuEpo therapy affects lipid metabolism, and whether these effects are influenced by changes in dietary habits and by route of rHuEpo administration. Methods. The study was performed in 33 maintenance haemodialysis patients (MHP) treated for one year with rHuEpo either intravenously (n = 15) or subcutaneously (n = 18), three times per week at the end of each dialysis session. The doses were 50 IU/kg intravenously or 35 IU/kg subcutaneously during the first 6 months and 20 IU/kg during the following months. The control group consisted of 17 MHP not treated with rHuEpo. Total cholesterol, LDL-cholesterol and HDL-cholesterol, triglycerides, apolipoproteins A1 and B, haemoglobin, serum albumin, blood urea nitrogen, serum creatinine, Kt/V, protein catabolic rate, and plasma erythropoietin were assessed at months 0, 2, 4, 6, 9, 12 and 2 weeks after rHuEpo discontinuation. Changes in food intake were evaluated on the basis of weekly dietary diaries before, and 3 and 9 months after treatment. Patients were divided into two groups: group A consisted of 19 patients who showed an increase in their energy intake (10% or more of basal value), and group B was formed by 14 patients without or with slight changes in their food intake. After the 6th month, dialysis schedules were adapted to new protein catabolic rate values in patients who increased their food intake. Results. During follow-up, there were no significant changes in any of the parameters in the control group. In group A, blood urea nitrogen, serum creatinine, protein catabolic rate, cholesterol, LDL cholesterol, triglycerides and apolipoprotein B increased significantly since the first months of rHuEpo treatment, and changes in cholesterol and apolipoprotein B correlated significantly with changes in protein catabolic rate. In group B, cholesterol, LDL cholesterol, and apolipoprotein B decreased significantly after the 6th month of treatment, without changes in blood urea nitrogen, serum creatinine and protein catabolic rate values. In both groups A and B, HDL cholesterol decreased significantly until the 6th month and returned to basal values in the following months and apolipoprotein A1 decreased until the 4th month and rose to levels higher than basal values in the following months. First rHuEpo administration and rHuEpo suspension at end of follow-up did not show any acute effect on lipid profile, despite significant changes in plasma erythropoietin values. Changes in lipid profile were similar with intravenous and subcutaneous administration of rHuEpo. Conclusions: We infer that long-term rHuEpo treatment positively affects the lipid profile, but in some patients who show exaggerated increase in their food intake these effects may be balanced and overcome by increment in some atherogenic blood lipid fractions. The changes in lipid and apolipoprotein patterns during rHuEpo therapy are not influenced by route of rHuEpo administration.     

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.     

Iron absorption in erythropoietin-treated haemodialysis patients; effects of iron availability, inflammation and aluminium

Background: The response to recombinant human erythropoietin (rHuEpo) is determined primarily by the availability of iron. In contrast to i.v. iron, oral iron supplementation is often insufficient for an optimal response. Method: We studied iron absorption and the effects of iron status, aluminium status and inflammation in 19 chronic haemodialysis patients on maintenance rHuEpo therapy. Iron mucosal uptake after 24 h, iron retention after 2 weeks and mucosal transfer of iron were determined with a whole-body counter using an oral dose ⁵⁹Fe. Iron absorption was measured once without, and once after the ingestion of 2 g aluminium hydroxide. Results: On the basis of transferring saturation, two groups of dialysis patients were distinguished: a group with a functional iron deficiency (n=9), and an iron-deficient dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 49.9%±29.4, 0.73±0.29, and 41.6%±32.2, being significantly lower than in a non-uraemic iron deficient population (P <0.01, P <0.05, P <0.01 respectively). In the iron-replete dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 20.0±12.3, 0.59±0.18, and 11.1±6.7, mucosal uptake and iron retention being lower than in a normal iron-replete population (P <0.0005 and P <0.003 respectively). Dialysis patients with high C-reactive protein (CRP) values showed lower iron absorption. Iron absorption data correlated significantly with transferrin saturation and CRP in the iron-deficient group, and with serum ferritin in the iron-replete group. Iron absorption decreased after an aluminium hydroxide challenge in the iron-deficient patients to the lower levels of the iron-replete subjects. Body aluminium stores, estimated by the desferrioxamine test, did not correlate with parameters of iron absorption. Conclusion: The absorption of iron in dialysis patients is decreased in haemodialysis patients, which may, at least in part, be due to inflammation. Aluminium ingestion further reduces absorption in functional iron-deficient patients. Key words: anaemia; erythropoietin; iron absorption; haemodialysis      

Desferrioxamine improves burst-forming unit-erythroid (BFU-E) proliferation in haemodialysis patients

Background: In chronic renal failure, desferrioxamine (DFO) may improve erythropoiesis independent from its aluminium (Al) chelating effect. The mechanism of this action is still unknown. Methods: To verify whether DFO influences proliferation of erythropoietic precursors, we studied 10 patients on chronic haemodialysis, free from malignancies or other haematological diseases, iron deficiency, bone marrow fibrosis, and Al toxicity. Al accumulation was excluded by the DFO test. Peripheral blood samples were drawn for basal burst-forming unit-erythroid (BFU-E) assay. Mononuclear cells were isolated by density gradient centrifugation with Ficoll-Hypaque, and incubated for 15 days with three different experimental conditions: (a) low-dose recombinant human erythropoietin (rHuEpo) (3 U/ml); (b) high dose rHuEpo, (30 U/ml); (c) both DFO (167 &mgr;g/ml) and rHuEpo (3 U/ml). We determined TIBC, transferrin, ferritin, reticulocytes, hypochromic erythrocytes, soluble transferrin receptor (sTR), haemoglobin (Hb), and haematocrit (Hct) at baseline and then every 14 days. Patients received 5 mg/kg DFO infused during the last hour of each dialysis session for 6 weeks; six patients remained in the study for an additional 6 more weeks. BFU-E assays were set up after 6 and 12 weeks of DFO therapy. Results: At baseline DFO had small effect on BFU-E proliferation (33.9±25 vs 30.4±25.9) and high-dose rHuEpo had a significant effect (45.15±27 vs 30.4±25.9, P<0.01). After 6 weeks of DFO therapy a significant increase in BFU-E proliferation was observed in all culture conditions (78.25±32 vs 30.45±25.9 standard culture, P<0.01; 110.9±30 vs45.15±27 high dose rHuEpo, P<0.01; 98.75±32 vs 45.15±27 DFO culture, P<0.01). Moreover, the increase in BFU-E proliferation was significant greater with DFO culture than standard culture (P<0.01). The same trend was found at the third BFU-E assay, performed in only six patients, when all culture conditions showed a further increase of erythroid precursor proliferation. However, the DFO culture was not significantly greater than the standard culture, while the high-dose rHuEpo was significantly greater than the DFO culture. Patients in group 1 (n=10), had a significant increase in reticulocytes (1.5±0.6 vs 1.72±0.3, P<0.01) and of hypochromic erythrocytes (HE) (5.6±5.1 vs 14.4±12.7, P<0.01), while sTR, Epo, Hb, and Hct were only minimally increased. Ferritin decreased significantly (448±224 vs 196±215, P<0.01) and TIBC and transferrin were unchanged. Conclusions: Thus DFO increases erythroid activity by BFU-E proliferation and increases reticulocytes in haemodialysis patients. Such an effect may be related to increased iron utilization. DFO may be a useful tool for anaemic patients with good iron stores and without Al overload. Key words: desferrioxamine; erythroid progenitors; erythropoiesis; haemodialysis      

The comparison of the diuretic and natriuretic efficacy of continuous and bolus intravenous furosemide in patients with chronic kidney disease

Aim: To compare natriuretic, kaliuretic, diuretic and free water clearance efficacy of continuous versus bolus intravenous furosemide administration in patients with chronic renal insufficiency. Material and methods: In a prospective randomized cross‐over trial, 42 patients of chronic renal insufficiency were randomized to receive the same dose of intravenous furosemide as bolus and continuous infusion. The effects of bolus and intravenous administration of furosemide on the volume of urine, sodium and potassium excretion were assessed. Results: Mean age was 53.6 ± 14 years and 23 (55%) were male. The mean modification of diet in renal disease glomerular filtration rate was 20.5 ± 17 mL/min per 1.73 m². The urinary excretion of sodium in intravenous bolus and infusion was 98.1 ± 78 and 114.4 ± 100 mmol, respectively (P = 0.001). Total urinary volume following bolus and infusion of furosemide was 1064 ± 627 and 1170 ± 764 mL, respectively (0.001). The excretion of potassium was similar in bolus (15.8 ± 16.6) and infusion (14.3 ± 9) administration (P = 0.11). The fractional excretion of sodium was higher following infusion (16.63 ± 16.1) than bolus administration (12.87 ± 9) of furosemide (P = 0.016). Conclusion: Continuous intravenous infusion of furosemide has significantly better natriuretic and diuretic effect than bolus administration of the same dose of the drug in patients with advanced chronic renal insufficiency.     

The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration (i.v. or s.c.)

Background: Previous studies comparing intravenous (i.v.) and subcutaneous (s.c.) administration of recombinant human erythropoietin (rHuEpo) often did not achieve optimal iron reserve, were restricted to a limited follow-up period (not allowing equilibration) and/or did not exclude the role of other confounding factors. In addition all papers focused on the conversion from i.v. to s.c. Methods: In this study, 30 equilibrated patients on s.c. rHuEpo were randomized into two groups, one converting to i.v. after 6 months of follow-up and one remaining on s.c. rHuEpo. In both groups rHuEpo was administered three times weekly. Only patients completing a further 6 months follow-up were considered for statistical evaluation. Serum ferritin was targeted at 200 ng/ml and haematocrits between 28 and 35% were pursued. Results: The average haematocrit levels before conversion were 31.9±1.1% in the conversion group and 31.4±1.6% at the same time point in the non-conversion group (P-NS). After 6 months haematocrits were 31.5±0.5% in the conversion group and 31.1±0.9% in the non-conversion group (P=NS). Ferritin concentration in the conversion group was 219±49 ng/ml before and 230±83 mg/ml after the conversion. For the non-conversion group ferritin was 224±25 ng/ml and 236±52 ng/ml respectively (P=NS). The weight-standardized average rHuEpo dose per injection remained the same in the conversion group before and after conversion (44.0±1.8 U/kg/injection vs 45.4±4.7 U/kg/injection) P=NS). In the non-conversion group the corresponding rHuEpo doses were 32.9±4.2 U/kg/injection and 39.6±7.0 U/kg/injection respectively (P=NS). There were no differences in serum PTH, aluminium, vitamin B12, folic-acid levels, and intake of co-trimoxazole, ACE inhibitors or theophylline. Conclusion: No changes in rHuEpo dose wee observed after conversion from s.c. to i.v. There were no significant differences between the conversion and non-conversion group. These results are in contrast to some earlier studies suggesting lower rHuEpo requirements in case of s.c. administration. Key words: anaemia; erythropoietin; intravenous erythropoietin; iron; subcutaneous erythropoietin      

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.     

Acute effects of recombinant human erythropoietin on plasma levels of proendothelin-1 and endothelin-1 in haemodialysis patients

Background: The pathogenesis of rHuEpo-induced hypertension in haemodialysis (HD) patients still remains uncertain. Endothelin-1 (ET-1) is produced from proendothelin-1 (proET-1) by an endothelin-converting enzyme. Since proET-1 is known to have approximately 1/100 the potency of ET-1 for contracting an isolated blood vessel, the change in the activity of endothelin-converting enzyme (ECE) has been proposed as an important factor in the pathophysiology of various hypertensive diseases. However there is no report on whether a change in the rate of conversion of proET-1 to ET-1 may be involved in the pathogenesis of rHuEpo-induced hypertension. The purpose of this study was to ascertain the potential role of ECE in the development of rHuEpo-induced hypertension. Methods: The levels of plasma erythropoietin, proET-1, ET-1, and mean arterial blood pressure (MAP) were measured following a single dose of rHuEpo (100 U/kg) in HD patients with 24-h ambulatory blood pressure monitoring. Different routes of administration (19 intravenous group, 10 subcutaneous group) were compared to a placebo-injected control group (10 HD patients). Results: Plasma erythropoietin levels reached maximal value 5 min after i.v injection of rHuEpo (13.1±2.4 vs 2780.9±290.1 mU/ml, P<0.01), whereas it was 6h in the s.c. group (14.7±3.8 vs 38.8±17.7 mU/ml, P<0.05). A significant increase in MAP was noted 30 min after rHuEpo injection, which lasted for 3 h in the i.v. group. However, no significant changes in MAP were noted in patients given rHuEpo subcutaneously. Both the plasma concentrations of proET-1 and ET-1 started to increase from 10 min after i.v. rHuEpo administration, with the pro-ET-1 reaching a peak level at 30 min (13.5±7.4 vs 21.6±3.8 pg/ml, P<0.05) and the ET-1 at 1 h (4.2±2.6 vs 9.9±4.8 pg/ml, P<0.05). In patients with significant interdialysis hypertension following a single i.v. injection of rHuEpo, the molar ratio of ET-1 over proET-1 (ET-1/proET-1) was significantly higher than in patients without hypertension. In addition, the increase in ET-1 levels was significantly greater in patients with interdialysis hypertension, while changes in proET-1 level were similar in both hypertensive and non-hypertensive groups. Changes in interdialysis MAP (Dgr;IDMAP) was significantly correlated with &Dgr;ET-1 during the interdialysis period, but not with &Dgr;proET-1. Conclusion: Differences in ET-1/proET-1 ratio in relation to changes in MAP after a single intravenous administration of rHuEpo suggest a potential role for ECE in the pathogenesis of rHuEpo-induced hypertension. Key words: endothelin-1; endothelin-converting enzyme; haemodialysis; proendothelin-1; rHuEpo-induced hypertension      

Increased visfatin in hemodialysis patients is associated with decreased demands for recombinant human erythropoietin

Abstract

Background: Studies detected an association between visfatin and markers of iron metabolism in patients with insulin resistance. In this study, such a relation was evaluated in hemodialysis (HD) patients. Also relations between visfatin and hepcidin, demands for recombinant human erythropoietin (rHuEpo), inflammation, and situations characterized by insulin resistance were evaluated. Methods: After a four-week washout period from iron treatment, 33 HD patients and 20 healthy volunteers enrolled in the study. Serum visfatin, hepcidin, and interleukin-6 (IL-6) were assessed by means of enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin, and transferrin saturation (TSAT) were also measured. Results: Visfatin was markedly increased in HD patients. Visfatin levels did not differ between diabetics and non-diabetics. No relation was detected between visfatin and body mass index or IL-6 in HD patients. From the markers of iron metabolism, the hepcidin included, visfatin was related only to TSAT. A strong positive relation was revealed between visfatin and hemoglobin, whereas visfatin was inversely related to rHuEpo dose. Resistance to rHuEpo index was inversely and independently of TSAT related to visfatin. Conclusion: Visfatin is increased in HD patients and it is associated with decreased demands for rHuEpo.     

Iron deficiency in patients with chronic kidney disease: potential role for intravenous iron therapy independent of erythropoietin

The prevalence of iron deficiency and its contribution to the anemia of end stage renal disease has been extensively studied, but much less is known about the role of iron deficiency in the pathogenesis of the anemia of chronic kidney disease in predialysis patients. All new hemodialysis patients entering a single hemodialysis unit between July 1999 and April 2002 were included in the study. The admission laboratory tests and the Health Care Financing Administration (HCFA) 2728 form were examined to determine the prevalence of erythropoietin use, anemia (Hb < 11 g/dl), and iron deficiency (ferritin < 100 ng/ml and transferrin saturation % < 20%). In a second part of the study, the effect of intravenous iron gluconate replacement in patients with stage III & IV chronic kidney disease was examined. Anemia was present in 68% of all patients starting hemodialysis. Iron deficiency was a common feature occurring in 29% of patients taking erythropoietin (49% of all patients) and 26% of patients without erythropoietin (51% of all patients). Following the administration of intravenous iron gluconate to four patients, there was a significant rise in hemoglobin levels from 10.6 ± 0.19 to 11.7 ± g/dl (p = 0.02). Conclusion: Iron deficiency is common in predialysis patients. Replenishing iron stores in anemic patients with chronic kidney disease significantly increases hemoglobin levels and should be considered as an integral part of the therapy for treating anemia in the predialysis population.     

Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities

Background: Before the routine use of recombinant human erythropoietin (rHuEpo), patients dialysed by peritoneal dialysis (PD) received fewer blood transfusions than patients on haemodialysis (HD). We compared transfusion practices in these groups now that the use of rHuEpo has become standard, while controlling for variables known to influence anaemia of end-stage renal disease (ESRD). Maintenance rHuEpo doses were also compared. Methods: Data were examined for 157 HD and 126 PD patients during a 2-year period. Potential confounders included age, gender, albumin, iron deficiency, parathyroid hormone (PTH), underlying renal disease, cormorbid illness, renal transplant, dialysis adequacy and duration. An intent-to-treat analysis was used, with sensitivity analyses to account for change in treatment and transplant. Results: Mean haemoglobin (Hb) was not different (10.47 g/dl for HD, 10.71 G/DL for PD; P=0.45). Mean monthly transfusion rate was higher for HD (0.47 units per month vs 0.19; P<0.01). More HD patients received at least one transfusion (52.9 vs 40.9%; P<0.01). The maintenance rHuEpo dose was higher for HD (7370 U/week vs 5790 U/week; P=0.01). The only factors associated with risk of being transfused were dialysis duration and mode of dialysis (less risk for PD, odds-ratio 0.57; 95% confidence interval 0.35-0.92). Conclusions: Despite the routine use of rHuEpo, HD patients received more blood and rHuEpo than PD patients to achieve the same Hb. No patient factors were identified to account for this difference. The use of fewer transfusions and less rHuEpo in PD represents an advantage over HD in terms of both cost and safety.     

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      

Efficacy and safety of a low monthly dose of intravenous iron sucrose in peritoneal dialysis patients

Purpose

Scientific data regarding intravenous iron supplementation in peritoneal dialysis (PD) patients are scarce. In attempting to administer the minimum monthly IV iron dose that could improve erythropoiesis, we wanted to assess the safety and efficacy of monthly maintenance intravenous administration of 100 mg iron sucrose in PD patients.

Methods

In a 9-month prospective study, all clinically stable PD patients received intravenously 200 mg of iron sucrose as a loading dose, followed by monthly doses of 100 mg for five consecutive months. Levels of hemoglobin (Hb), ferritin, transferrin saturation (TSAT), reticulocyte hemoglobin content (CHr) and C-reactive protein (CRP) were measured before each administration and 3 months after the last iron infusion. Also, doses of concurrent erythropoietin administration were recorded.

Results

Eighteen patients were eligible for the study. Mean levels of Hb and ferritin increased significantly (from 10.0 to 10.9 mg/dL, p?=?0.01 and from 143 to 260 ng/mL, p?=?0.005), as well as the increase in TSAT levels approached borderline significance (from 26.2 to 33.1%, p?=?0.07). During the 6 months of iron administration, the erythropoietin dose was reduced in five patients and discontinued in one. During the 3 months following the last iron infusion, three of them again raised the erythropoietin dose to previous levels. None of the patients experienced any side effects related to IV iron administration.

Conclusions

A monthly maintenance intravenous dose of 100 mg iron sucrose may be a practical, effective, and safe in the short term, treatment of anemia in PD patients resulting in improved hemoglobin levels, iron indices, and erythropoietin response.

     

Alteration of mRNA expression of molecules related to iron metabolism in adenine-induced renal failure rats: a possible mechanism of iron deficiency in chronic kidney disease patients on treatment.

BACKGROUND: Recombinant human erythropoietin (rHuEpo) is a definitive treatment for anaemia in chronic kidney disease (CKD). During long-term rHuEpo treatment most patients develop and show persistent iron deficiency in spite of oral iron supplementation. Abnormalities of iron absorption and transport in the duodenum may contribute to this deficiency. METHODS: To investigate changes in iron absorption and transport in CKD and iron deficiency against the background of rHuEpo treatment, we used severely anaemic rats with adenine-induced renal failure (adenine rats) and sham-treated control rats given only the vehicle. After 4 weeks on adenine or the vehicle, the rats were divided into four groups according to whether or not they received rHuEpo for the next 4 weeks: rHuEpo(-)-adenine, rHuEpo(-)-control, rHuEpo(+)-adenine and rHuEpo(+)-control. We evaluated the effects of rHuEpo treatment on iron balance, duodenal mRNA expression of molecules related to iron absorption and transport and hepatic mRNA expression of hepcidin. RESULTS: Treatment with rHuEpo improved anaemia and induced iron deficiency only in the adenine rats, in whom the expression of mRNAs for ferroportin 1 and hephaestin 1 increased and for divalent metal transporter 1 (DMT1) was unchanged. In contrast, control rats treated with rHuEpo showed no changes. Hepcidin mRNA expression was greater in adenine rats than in control rats. CONCLUSIONS: In the adenine rats, rHuEpo treatment improved renal anaemia and induced persistent iron deficiency. An alteration of mRNA expression of molecules related to iron metabolism in renal insufficiency may be one of the reasons for this iron deficiency.     

Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients.

BACKGROUND: Optimal response to recombinant human erythropoietin (rHuEpo) in haemodialysis (HD) patients requires provision of sufficient available iron. However, a balance between iron requirements and supplements remains a challenge in clinical practice. Reticulocyte parameters, i.e. reticulocyte haemoglobin content (CHr) and reticulocytes in a high-fluorescence intensity region (HFR), have been shown to be accurate predictors of iron-deficient erythropoiesis as compared with traditional markers. Therefore, the aim of this study was to appraise the diagnostic power of these two parameters in the early prediction of response to intravenous iron (IVFE) medications in HD patients receiving rHuEpo. METHODS: Sixty-five HD patients with a serum ferritin level of <500 microg/l and on rHuEpo therapy for >6 months were enrolled for IVFE supplementation (100 mg iron saccharate three times a week for 4 weeks, then 100 mg every 2 weeks for 5 months). Haemoglobin, haematocrit, serum ferritin, transferrin saturation, reticulocyte count, percentage of hypochromic red cells, CHr and HFR were measured before and following iron supplementation. Response was defined as a rise in haematocrit of >3% and/or a reduction in rHuEpo dose of >30% over the baseline values at the end of the study. RESULTS: Forty-two patients had a dramatic response to IVFE therapy with a 13.5% increase in mean haematocrit and a 38% reduction in rHuEpo dose at the end of the study (P<0.001). This paralleled a statistically significant rise in CHr and HFR (P<0.001). Univariate analyses showed that ferritin (P<0.010) and CHr (P<0.001) at baseline, changes in CHr (DeltaCHr(2W), P<0.001) and HFR (DeltaHFR(2W), P<0.010) at 2 weeks, as well as changes in CHr (DeltaCHr(4W), P<0.001) and HFR (DeltaHFR(4W), P<0.001) at 4 weeks, strongly correlated with response to IVFE supplementation. Stepwise discriminant analysis disclosed that DeltaCHr(4W) in conjunction with DeltaHFR(4W) exhibited an r(2) value of 0.531 (P<0.001) to predict response to IVFE therapy. Analyses by receiver operating characteristic curves and logistic regression further revealed that DeltaCHr(4W) at a cut-off value of >1.2 pg and DeltaHFR(4W) of >500/microl were more specific to the status of iron-deficient erythropoiesis following IVFE medications. Combined use of the two cut-off values allowed for the highest accuracy in the early prediction of the response to IVFE therapy, with a sensitivity of 96% and a specificity of 100%. CONCLUSIONS: Our study shows that changes in CHr and HFR at either 2 or 4 weeks are superior to the conventional erythrocyte and iron metabolism indices and may serve as reliable parameters to detect iron-deficient erythropoiesis in HD patients undergoing rHuEpo therapy. During aggressive IVFE treatment, early identification of non-responsiveness and subsequent discontinuation of treatment can avoid the inadvertent iron-related toxicity due to over-treatment.     

Economic appraisal of maintenance parenteral iron administration in treatment of anaemia in chronic haemodialysis patients

BACKGROUND.: Iron deficiency is common in haemodialysis patients and adequatesupplementation by the oral or parenteral route has been limitedby drug side-effects, absorption, and cost. Intermittent doses of intravenous iron dextran complex are recommendedin patients with inadequate iron stores despite maximal toleratedoral dose. We conducted a prospective study with economic analysisof a regular maintenance intravenous iron regimen in this groupof patients. METHODS.: Fifty patients comprising one-half of our haemodialysis populationrequired intravenous iron treatment, i.e. they failed to achievean arbitrary goal serum ferritin 100 µg/l despite maximaltolerated oral iron dose. After a loading dose of intravenousiron dextran complex (IV-FeD) based on Van Wyck's nomogram (400±300mg) they received a maintenance dose of 100 mg IV-FeD once every2 weeks. Initial goal serum ferritin was set at 100–200µg/l. If no increase in haemoglobin was achieved at thislevel, transferrin saturation was measured to assess bioavailableiron, and when less than 20%, goal serum ferritin was increasedto 200–300 µg/l. Recombinant human erythropoietin(rHuEpo) was used where needed to maintain haemoglobin in the9.5–10.5 g/l range only if ferritin requirements weremet. RESULTS.: Mean haemoglobin rose from 87.7±12.1 to 100.3±13.1g/l (P<0.001, Cl 7.7–17.9) at mean follow-up of 6 months(range 3–15 months). In patients on rHuEpo, dose per patientwas reduced from 96±59 u/kg per week to 63±41u/kg per week, repres enting a 35% dose reduction (P<0.05,Cl 1–65). An annual cost reduction of $3166 CDN was projected;however, in the first year this is offset by the cost of theloading dose of IV-FeD required at the beginning of treatment.No adverse reactions were encountered. CONCLUSIONS.: Iron deficiency is very common in our haemodialysis population,especially in those patients receiving rHuEpo. A carefully monitoredregimen of maintenance parenteral iron is a safe, effective,and economically favourable means of iron supplementation inpatients with insufficient iron stores on maximum toleratedoral supplements.     

Aluminium interference in the treatment of haemodialysis patients with recombinant human erythropoietin

In nine chronic haemodialysis patients a desferrioxamine (DFO) load test (40 mg/kg body-weight) was performed 1 year after the beginning of treatment with recombinant human erythropoietin (rHuEpo). The patients were then divided into two groups. Group A comprised five patients with a greater mean aluminium (204 +/- 28 micrograms/l) than the four patients in group B. Group A was given a mean dose of 25.8 g (range 14-39 g) of DFO over 6 months. Group B (aluminium values 112 +/- 36 micrograms/l) was never treated with DFO. During the period of observation, plasma iron, serum ferritin and transferrin, as well as iron supplementation, did not differ between the groups. After DFO treatment a second DFO load test was performed. The mean predialysis aluminium value was significantly reduced in group A (204 +/- 28 vs 111 +/- 72 micrograms/l; P less than 0.05), while remaining unchanged in group B (112 +/- 36 vs 140 +/- 39 micrograms/l; P = ns). In both groups, the doses of rHuEpo necessary to maintain the same haemoglobin values decreased with time, but reduced significantly only in group A (298 +/- 105 vs 110 +/- 61 mu/kg per week; delta -63%; P less than 0.01). Thus, aluminium interferes with the response to rHuEpo in haemodialysis patients, and the correction of aluminium overload with DFO can allow a considerable sparing of rHuEpo.     

Kinetics of erythropoiesis in dialysis patients receiving recombinant erythropoietin treatment

In eleven patients with uraemia on intermittent haemodialysis treatment, recombinant human erythropoietin (rHuEpo) was used at a dosage schedule of 100 IU/kg bodyweight thrice weekly. Erythrokinetic studies (blood volume, RBC survival and iron kinetics) were performed in nine cases before and after 6 months of treatment. The remaining two patients had only RBC and plasma volume determinations before and after treatment. Although total blood volume remained unchanged, RBC volume was increased in all cases. Red cell loss was not modified, and quantitative improvement of RBC production was noted in all cases. No qualitative defect of erythroid maturation or release was observed in the treated patients. In conclusion, rHuEpo treatment improves the anaemia of haemodialysis patients by normalising circulating RBC volume only through an increase in red cell production.