Safety of intravenous injection of iron saccharate in haemodialysis patients

BACKGROUND.: The most frequent i.v. iron preparations used for haemodialysispatients are iron dextran, iron gluconate and iron saccharate.Possible side effects include anaphylactic reactions due topreformed antibodies to dextran or vascular reactions due tounbound iron during treatment with iron gluconate or iron saccharate. METHODS.: Four dosage regimens of i.v. iron saccharate therapy were studied:10, 20, 40 and 100 mg, which were given over a time period of1 min after the end of the dialysis session. Iron metabolismparameters (serum iron concentration, transferrin saturationand serum ferritin levels) were measured at 0, 1, 5, 15 and30 min after application and immediately prior to the next dialysissession. All 18 regular haemodialysis patients studied receivedrecombinant human erythro-poietin (rHuEpo). RESULTS.: Serum iron levels and transferrin saturation increased significantlyfollowing i.v. injection of all doses of iron saccharate. Iron‘oversaturation’ of transferrin iron binding didnot occur in patients with transferrin levels >180 mg/dl.However, in patients with transferrin levels <180 mg/dl theinjection of 100 mg iron saccharate resulted in a transferrinsaturation of 102.6±39.5% (two patients with transferrinlevels of 87 and 92 mg/dl had transferrin saturations of 119.8and 149.7%, two patients with transferrin levels of 148 and171 mg/dl had transferrin saturations of 77.9 and 63.1%, respectively).Serum ferritin levels remained unchanged during the post-injectionperiod and increased by the next dialysis session followinginjection of 100 mg iron saccharate by 165%. CONCLUSIONS.: It is concluded that intravenous iron saccharate injection (10–100mgeven within 1 min) does not result in ‘oversaturation’of transferrin iron binding if serum transferrin levels are>180mg/dl (high-risk patients: transferrin <100 mg/dl). Thismay explain, at least in part, the minimal side effects observedduring the i.v. application of iron saccharate. Low-dose i.v.iron saccharate (10–40 mg) is recommended for iron supplementationof haemodialysis patients. If injection of 100 mg is necessary,serum transferrin level should exceed 180 mg/dl. There is, however,no need for fast i.v. injection during routine iron supplementation.     

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.     

Efficacy of low‐dose i.v. iron therapy in haemodialysis patients

Aim: i.v. iron therapy is more effective in maintaining adequate iron status in haemodialysis (HD) patients than oral iron therapy (OIT). However, data on lower doses of i.v. iron therapy are insufficient. Methods: A non‐randomized, open‐label study was performed to compare the efficacy of low‐dose (≤50 mg/week of iron sucrose) i.v. iron therapy (LD‐IVIT) with OIT in HD patients with 100–800 µg/L serum ferritin levels over 4 months. Results: Eighty‐nine patients in the LD‐IVIT group (40 men, 49 women; aged 61 ± 13 years) and 30 patients in the oral iron therapy group (17 men, 13 women; aged 59 ± 7 years) were evaluated. After 4 months of each treatment, serum ferritin levels increased from 398 ± 137 to 529 ± 234 µg/L in the LD‐IVIT group (P < 0.01) but decreased from 351 ± 190 to 294 ± 175 µg/L in the OIT group (P < 0.01). In the LD‐IVIT group, transferrin saturation (from 28% ± 11% to 30% ± 14%, P = 0.49), weekly doses of recombinant human erythropoietin (from 5822 ± 2354 to 5636 ± 2306 IU/week, P = 0.48) and haemoglobin (from 101 ± 9 to 103 ± 9 g/L, P = 0.15) levels remained stable. Conclusion: LD‐IVIT may be one of the regimens that may be considered for maintaining iron status in HD patients. However, efficacy of LD‐IVIT should be verified by further randomized study.     

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.     

Randomized clinical trial on acute effects of i.v. iron sucrose during haemodialysis

Aim: Haemodialysis induces endothelial dysfunction by oxidation and inflammation. Intravenous iron administration during haemodialysis could worsen endothelial dysfunction. The aim of this study was to ascertain if iron produces endothelial dysfunction and the possible neutralizing effect of N‐acetylcysteine when infused before iron. The oxidative and inflammatory effects of iron during haemodialysis were also assessed. Methods: Forty patients undergoing haemodialysis were studied in a randomized and cross‐over design with and without N‐acetylcysteine infused before iron sucrose (50 or 100 mg). Plasma Von Willebrand factor (vWF), soluble intercellular adhesion molecule‐1 (sICAM‐1) levels, malondialdehyde, total antioxidant capacity, CD11b/CD18 expression in monocytes, interleukin (IL)‐8 in monocytes and plasma IL‐8 were studied at baseline and during haemodialysis. Results: Haemodialysis produced significant (P < 0.001) increase in plasma vWF, sICAM‐1, malondialdehyde, IL‐8 and CD11b/CD18 expression in monocytes, as well as decrease in total antioxidant capacity. Iron induced significant increase in plasma malondialdehyde and IL‐8 in monocytes, but had no effect on total antioxidant capacity, CD11b/CD18 expression, plasma IL‐8, vWF and sICAM‐1. The addition of N‐acetylcysteine to 50 mg of iron produced a significant (P = 0.040) decrease in malondialdehyde. Conclusion: Standard (100 mg) and low (50 mg) doses of iron during haemodialysis had no effects on endothelium. Iron only had minor effects on inflammation and produced an increase in oxidative stress, which was neutralized by N‐acetylcysteine at low iron dose. Haemodialysis caused a significant increase in oxidative stress, inflammation and endothelial dysfunction markers.     

Low-dose continuous iron therapy leads to a positive iron balance and decreased serum transferrin levels in chronic haemodialysis patients

Background. Iron balance is critical for adequate erythropoiesis,but its optimal therapeutic regimen remains to be defined. Continuousmaintenance therapy with iron has been proposed for dialysispatients on recombinant human erythropoietin (rHuEpo) in thehope that the regimen is adequate and safe. Methods. We determined serum ferritin, transferrin, transferrinsaturation (TSAT), serum transferrin receptors, albumin andC-reactive protein (CRP) in a 3-year prospective study in 30chronic haemodialysis patients on dialysis treatment for 132±111months (18 males, 12 females; mean age 56±14 years).Beginning in the year 2000, they regularly received low-dosemaintenance iron supplementation (i.v. iron gluconate 31.25mg/week) for 12 months (Period 1 or first treatment phase),followed by a 6-month withdrawal (Period 2 or stop phase) andthen by continuous maintenance iron therapy (i.v. iron gluconate31.25 mg/week) for another 9 months (Period 3 or re-challengephase). Results. A significant increase in serum ferritin and TSAT wasobserved, with values exceeding 500 ng/ml and 50% in 10/30 (33%)and 7/30 (23%) of subjects, respectively, in Period 1, and in11 and 5% in Period 3. A significant decrease in serum transferrinwas documented during Period 1, followed by an increase in Period2 and a decrease in Period 3. Serum albumin remained stable.Serum transferrin was always negatively correlated with ferritin(r = –0.41, P<0.001) and weakly correlated with serumtransferrin receptors (r = 0.178, P<0.05), but was not correlatedwith serum albumin or CRP. Regression equations based on pre-treatmentserum ferritin values were developed for predicting the valueof serum ferritin at any time following the beginning of continuousiron supplementation. They fitted a linear relationship formales (y = 81 + 21.5 x time) and for females (y = 65 + 22 xtime). Percentile charts for quantitative tracking of serumferritin increases and decreases in patients have also beendeveloped from values measured at different times. These chartsshow box-plot distributions of expected ferritin against time. Conclusions. Even continuous low-dose maintenance iron therapy,with only 31.25 mg weekly over 1 year, cannot prevent the riskof iron overload in patients with moderate anaemia. Furthermore,this treatment is responsible for decreases in serum transferrin,unrelated to changes in serum albumin, possibly of concern forhypo-transferrinaemia as an independent risk factor for irontoxicity.     

Inflammation and pruritus in haemodialysis patients.

BACKGROUND: Pruritus is a common symptom among patients on haemodialysis (HD). We studied 68 HD patients to assess the role of iron deficiency, anaemia, inflammation and other common serum and dialysis parameters in pruritus. METHODS: The patients were questioned about the occurrence of pruritus at home, quantified according to frequency ('never', 'occasionally' and 'every day') and intensity ('absent', 'moderate' and 'severe'). The blood and serum variables considered were: haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, hypochromic red blood cells (RBC), hyperchromic RBC, microcytic RBC, macrocytic RBC, reticulocytes, iron, ferritin, transferrin, transferrin saturation, C-reactive protein (CRP), urea, creatinine, calcium, phosphorus, albumin, total protein and glucose. We also analysed Kt/V, age and time on HD treatment. Patients were divided into 3 groups according to the frequency or intensity of their pruritus, and we analysed and compared the variables between the 3 groups. RESULTS: Half (50%) of the patients reported never having pruritus, 32.4% occasionally and 17.6% every day. Pruritus was moderate in 41.2% of them and severe in 8.8%. None of the parameters considered revealed any statistically relevant differences between the three pruritus frequency groups, except for mean serum transferrin level (mg/dl) ('never'=268+/-64 vs 'occasionally'=244+/-40 vs 'every day'=217+/-56, P<0.05). As for the intensity of the symptom, mean serum transferrin (268+/-64 vs 247+/-39 vs 174+/-31, P<0.001) and median ferritin levels (mg/dl) (83 (11-420) vs 98 (11-1121) vs 293 (111-471), P<0.05) showed statistically significant differences between the 3 groups, as did albumin levels (g/dl) (4.3+/-0.4 vs 4.2+/-0.4 vs 3.7+/-0.4, P<0.05). Median CRP values (mg/dl) tended to be higher in patients with more frequent (0.4 (0.3-5.5) vs 0.7 (0.3-11.4) vs 0.9 (0.3-13.5)) and more severe pruritus (0.4 (0.3-5.5) vs 0.7 (0.3-4.0) vs 2.1 (0.3-13.5)), but those differences were not statistically significant. CONCLUSIONS: Iron deficiency and anaemia seem to play no part in HD-related pruritus, whereas lower serum transferrin and albumin levels and higher ferritin values are consistent with the possible role of inflammation in the development and severity of pruritus.     

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.     

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.     

Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey

All adult patients from 13 dialysis centres were prospectivelyfollowed up for 6 months in an attempt to appraise the currentrisk factors for bacterial infections in stable chronicallyhaemodialysed patients. Parameters recorded as potential riskfactors for BI were age, gender, cause of renal failure, timeelapsed since the start of dialysis, history of transplantation,recent surgical procedure, previous bacterial infection, currentimmunosuppressive or erythropoietin therapy, type of angioaccessdevice, and serum ferritin level. Six hundred and seven patients(mean age 56.5 years, range 18–85) were enrolled in thestudy. Mean time elapsed since the start of dialysis was 4.7years. One hundred and eighteen patients had developed at leastone bacterial infection during the study period whereas 489had remained free of bacterial infection at the end of the follow-up.In multivariate analysis three parameters were found to be significantand independent risk factors for bacterial infection: previoushistory of bacterial infection (at least one versus no previousepisode), type of angioaccess device (catheter versus nativefistula), and elevated serum ferritin level (greater versuslower than 500 µg/l). These results support the evidencethat impaired host defences in chronic haemodialysis patientsmay be secondary to the dialysis procedure and suggest thatthe incidence of bacterial infection in these patients may befurther reduced by appropriate supportive therapy.     

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.     

Monitoring of iron requirements in renal patients on erythropoietin

We studied 38 patients (9 haemodialysis, 18 peritoneal dialysis,11 advanced renal failure) over the first 12 weeks of erythropoietintherapy. In 14 iron-overloaded patients (ferritin >500 µg/l)the haemoglobin (±SEM) increased from 6.74±0.27to 9.85±0.36 g/dl (P<0.0001) entirely by mobilizingiron reserves (reduced from 1,220±73 to 739±111mg, P<0.0001). In the 24 non-overloaded patients (ferritin<500µg/l) the haemoglobin rose similarly from 7.04±0.18to 10.70±0.36 g/dl (P<0.0001), partly from iron reserves(depleted from 200±74 to –44±77mg, P=0.016)and partly from oral iron supplements (305±110 mg). Inthe overloaded patients the ferritin declined from 1057 µg/l(geometric mean, range 504–3699) to 317 µg/l (42–1505,P<0.0001). In the non-overloaded patients it declined from82 µg/l (8–461) to 45 µg/l (5–379, P=0.016).The transferrin saturation (TS) in the overloaded patients appearedto decline from 38.3±7.2% to 24.0±3.7% but thiswas not statistically significant. In the non-overloaded theTS was unchanged (23.3±2.4 before and 28.1±3.6%after treatment). Considering all 38 patients together, thehaemoglobin correlated negatively with the ferritin (r=0.3731,P<0.001) but not with the TS. The TS correlated with theserum ferritin initially (r=0.75, P<0.001) but not afterthe first 4 weeks. At 12 weeks, eight of 15 patients with irondeficiency (ferritin<50 µg/l) had a TS >20%, whereastwo of five patients with persistent iron overload (ferritin>500 µg/l) had a TS <20%. We conclude that (a) inpatients with iron overload, stored iron is utilizable for erythropoiesis;(b) oral iron supplements are necessary and sufficient for mostpatients without iron overload; (c) the serum ferritin is abetter indicator of iron status than the TS for renal patientson erythropoietin.     

Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-replete haemodialysis patients.

BACKGROUND: Haemodialysis patients need sustained treatment with intravenous iron because iron deficiency limits the efficacy of recombinant human epoetin therapy in these patients. However, the optimal intravenous iron maintenance dose has not been established yet. METHODS: We performed a prospective multicentre clinical trial in iron-replete haemodialysis patients to evaluate the efficacy of weekly low-dose (50 mg) intravenous iron sucrose administration for 6 months to maintain the iron status, and to examine the effect on epoetin dosage needed to maintain stable haemoglobin values in these patients. Fifty patients were enrolled in this prospective, open-label, single arm, phase IV study. RESULTS: Forty-two patients (84%) completed the study. After 6 months of intravenous iron sucrose treatment, the mean ferritin value showed a tendency to increase slightly from 405 +/- 159 at baseline to 490 +/- 275 microg/l at the end of the study, but iron, transferrin levels and transferrin saturation did not change. The haemoglobin level remained stable (12 +/- 1.1 at baseline and 12.1 +/- 1.5 g/dl at the end of the study). The mean dose of darbepoetin alfa could be reduced from 0.75 to 0.46 microg/kg/week; epoetin alfa was decreased from 101 to 74 IU/kg/week; and the mean dose of epoetin beta could be reduced from 148 to 131 IU/kg/week at the end of treatment. CONCLUSIONS: A regular 50 mg weekly dosing schedule of iron sucrose maintains stable iron stores and haemoglobin levels in haemodialysed patients and allows considerable dose reductions for epoetins. Low-dose intravenous iron therapy may represent an optimal approach to treat the continuous loss of iron in dialysis patients.     

Oxidative stress from rapid versus slow intravenous iron replacement in haemodialysis patients

METHODS AND RESULTS: Oxidative stress was examined in 19 erythropoietin-treated haemodialysis patients who were receiving 100 mg of iron sucrose every 2 weeks by two intravenous methods, rapid injection and slow infusion. There were no significant differences in incidence of iron oversaturation state between the two methods. Regarding oxidative stress markers, the values of plasma and red blood cell thiobarbituric acid reactive substances (TBARS) expressed in terms of malonyldialdehyde (MDA) equivalents following the two methods did not increase, and the values of area under the curve (AUC) of both markers were not different between both regimens. Also, there were no significant differences in the values of plasma and AUC of anti-oxidant markers including total anti-oxidant status, reduced thiols, and vitamin E among both periods treated with two intravenous iron methods. CONCLUSION: As such, both intravenous iron methods could be safely used without enhancing oxidative stress in haemodialysis patients. The rapid injection method would be the preferred method of intravenous iron administration because it is more convenient while still retaining the safety profile.     

Determinants of circulating soluble transferrin receptor level in chronic haemodialysis patients.

BACKGROUND: The aim of this study was to identify the factors determining the circulating soluble transferrin receptor (sTfR) concentrations in haemodialysis (HD) patients on maintenance recombinant human erythropoietin (rHuEpo) treatment. METHODS: In a prospective cross-sectional study, 91 chronic HD patients and 18 anaemic controls with normal renal function were recruited. For each subject, blood samples were measured for complete blood count, reticulocyte count, percentage of hypochromic red cells (% HRC), serum ferritin, serum iron, transferrin saturation (TS), serum erythropoietin (sEpo), C-reactive protein (CRP), and sTfR. HD patients received constant rHuEpo doses and basal sEpo was measured > or = 86 h after the last injection. The age, gender, dialysis vintage, and the above-mentioned parameters were used as independent variables and logarithmic sTfR (log(10)sTfR) as a dependent variable in the forward stepwise multiple regression model. RESULTS: HD patients were similar to controls regarding haematocrit, serum ferritin, TS, and % HRC, but had significantly lower sTfR, sEpo, and reticulocyte index. Univariate analyses showed that the sTfR level strongly correlated with sEpo (r=0.60, P<0.001) and % HRC (r=0.60, P<0.001), and significantly with serum ferritin (r=-0.29, P<0.01), TS (r=-0.27, P<0.05), and dose of rHuEpo administered (r=0.27, P<0.05) in HD patients. sTfR also had a positive correlation with haematocrit (r=0.26, P<0.05), red blood cell (RBC) count (r=0.23, P<0.05), and reticulocyte count (r=0.24, P<0.05), but not with CRP (r=0.16, P>0.05). Multivariate regression analysis disclosed that sEpo, HRC, and serum ferritin were the independent predictors of sTfR level. Overall, the model explained 58.8% of the variability in sTfR (R(2)=0.588, P<0.001). CONCLUSIONS: Circulating sTfR is a good index of marrow erythropoietic activity in HD patients during rHuEpo treatment. Its level is also independently up-regulated by functional iron deficiency in the process of enhanced erythropoiesis. Our study showed that sTfR levels quantitatively reflect the integrated effects of iron availability, iron reserves, and erythropoietic stimulation.     

'Oversaturation' of transferrin after intravenous ferric gluconate (FerrlecitR) in haemodialysis patients

BACKGROUND: Chronic haemodialysis causes blood loss and iron-deficiency.This can be corrected with intravenous preparations, e.g. sodiumferric-gluconate (FeGl). In two patients complaints of hypotensionand malaise during FeGl infusion coincided with high levelsof serum iron and a calculated transferrin iron saturation above100%. Iron toxicity could be the cause of these complaints.Free iron is known to aggravate the toxicity of free radicalsand other reactive oxygen products that are constantly formedin the body. We compared four rates of FeGl infusion with regardto iron parameters. METHODS: 20 dialysis patients received a total of 36 infusions of FeGl.A rapid infusion of 125 mg (Protocol A (n=10)) or 62.5 mg (ProtocolB (n=7)) of FeGl was given during the last 30 min of dialysis.A slow infusion of 125 mg (Protocol C (n=9)) or 62.5 mg (ProtocolD (n=10)) was given during 4 or 4.5 h of dialysis. Blood wastaken at regular intervals before, during, and after dialysisfor determination of serum iron, transferrin, ferritin, haematocrit,total protein, albumin, and lactate dehydrogenase (LDH). Transferrinsaturation was calculated from transferrin and serum iron. RESULTS: With rapid infusion A (125mg) the highest levels of serum iron(median 120 (range 40–159) micromol/l) and transferrinsaturation (207 (84–331)%) were seen at the end of theinfusion. These were significantly higher than the peak levelswith B, C, and D (P0.03). With rapid infusion B (62.5 mg), peaklevels were intermediately high (serum iron 61 (50–96)µmol/l; transferrin saturation 118 (91–174)%). Withslow infusion C (125 mg) similar peak levels were seen (serumiron 83 (43–106) µmol/l; transferrin saturation141 (88–172)%). With slow infusion D (62.5 mg), the lowestpeak levels were seen (serum iron 38 (31–55) µmol/l;transferrin saturation 78 (43–92)%). These levels weresignificantly lower than those with A, B and C (p0.002). Onlywith D all patients showed a transferrin saturation lower than100%. Ferritin was increased before the next dialysis in allpatients. LDH was not significantly elevated during any infusion. CONCLUSIONS: The commonly used rapid infusion rate (A) of FeGl causes ‘oversaturation’of transferrin. This is compatible with iron toxicity due tofree iron which may explain our patients' complaints. Free ironcannot be measured directly. LDH as a crude measure of celldamage was not elevated. Better measurements to prove free irontoxicity, like lipid peroxides, are not yet readily available.Infusion during a longer period at a lower dose (D) is effectiveand eliminates ‘oversaturation’ of transferrin andprobably the danger of iron toxicity.     

Two different modalities of iron gluconate i.v. administration: effects on iron, oxidative and inflammatory status in peritoneal dialysis patients.

BACKGROUND: Iron deficiency represents an important problem for dialysis patients. Oral iron administration is frequently ineffective, requiring parenteral administration, which may trigger severe side effects due to inflammation and/or peroxidation. The aim of the present study was to clarify the effects of parenteral iron administration on iron, inflammatory and oxidative status in peritoneal dialysis patients and compare two different modalities of injecting ferric gluconate intravenously. METHODS: Twenty peritoneal dialysis patients (10M/10F, mean age 60 +/- 16 years) were given i.v. iron gluconate (62.5 mg) both concentrated (1-2 min, PULSE) and diluted in 100 ml of glucose solution (30 min, SLOW). The interval between the first and second administration was 15-60 days. Blood cell count, serum iron, total iron binding capacity (TIBC), ferritin, C-reactive protein (CRP), reactive oxygen species (ROS) concentrations and total antioxidant capacity (TAC) were measured before iron infusion (T0), after 30 min (T1) and after 24 h (T2). RESULTS: No patient had clinical symptoms during or within an hour of iron administration. Serum transferrin was oversaturated in 25% of cases, no matter how iron was injected. Oxidative and inflammatory status parameters were not affected by iron administration: no difference in CRP, ROS concentrations or TAC was found at any time between PULSE and SLOW group. CONCLUSIONS: Our findings showed that neither inflammation nor peroxidation in peritoneal dialysis patients was clinically triggered by 62.5 mg i.v. iron infusion. Both modalities were equally safe. Therefore, in the absence of clinical side effects, PULSE intravenous administration, being cheaper and not so problematic for outpatients, is preferable to SLOW.