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.     

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.     

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.     

Catalytically active iron and bacterial growth in serum of haemodialysis patients after i.v. iron-saccharate administration.

BACKGROUND: I.v. iron is commonly administered to haemodialysis patients suffering from anaemia to improve their response to erythropoietin therapy. It has been unclear whether routinely used doses of i.v. iron preparations could result in iron release into plasma in amounts exceeding the iron binding capacity of transferrin. Here, we have studied the effect of 100 mg of iron saccharate given as an i.v. injection on transferrin saturation and the appearance of potentially harmful catalytically active iron. METHODS: We followed serum iron, transferrin and transferrin-saturation before and 5-210 min after administration of iron saccharate in 12 patients on chronic haemodialysis due to end-stage renal disease. We measured catalytically active iron by the bleomycin-detectable iron (BDI) assay and transferrin iron forms by urea gel electrophoresis, and studied iron-dependent growth of Staphylococcus epidermidis inoculated into the serum samples in vitro. RESULTS: The iron saccharate injection resulted in full transferrin saturation and appearance of BDI in the serum in seven out of the 12 patients. BDI appeared more often in patients with a low serum transferrin concentration, but it was not possible to identify patients at risk based on serum transferrin or ferritin level before i.v. iron. The average transferrin saturation and BDI level increased until the end of the follow-up time of 3.5 h. The appearance of BDI resulted in loss of the ability of patient serum to resist the growth of S. epidermidis, which was restored by adding iron-free apotransferrin to the serum. Iron saccharate, added to serum in vitro, released only little iron and promoted only slow bacterial growth, but caused falsely high transferrin saturation by one routinely used serum iron assay. CONCLUSIONS: The results indicate that 100 mg of iron saccharate often leads to transferrin oversaturation and the presence of catalytically active iron within 3.5 h after i.v. injection. As catalytically active iron is potentially toxic and may promote bacterial growth, it may be recommendable to use dosage regimens for i.v. iron that would not cause transferrin oversaturation.     

Factor Deficiency in the Anemia of Renal Transplant Patients With Grade III-IV Chronic Kidney Disease: Baseline Results of the ARES Study

ARES is a multicenter, prospective study of the prevalence, management, and repercussions on the quality of life of anemia in renal transplant patients with a reduced renal function (creatinine clearance according to Cockcroft-Gault: ≤60 and >15 mL/min). The frequency of factor deficiency and its relationship with anemia were analyzed at the baseline time of the study. Of the 500 patients included in the main study, valid data were available for iron metabolism in n = 419 μg/dL; folic acid, n = 205 ng/mL; and vitamin B12, n = 210 pg/mL. Anemia was defined as hemoglobin ≤13 g/dL (men) or ≤12 g/dL (women) and/or use of erythropoietin (EPO). Anemic patients (59.4%) had less sideremia (73.4 vs 81.2 μg/dL; P = .008), but no significant differences were observed for transferrin saturation index (25.9% vs 25.5%), ferritin (167 vs 171 ng/mL), iron insufficiency (26.5% vs 36.2%), pronounced ferropenia (20.4% vs 20.1%), folic acid (7.5 vs 6.6 ng/mL), or vitamin B12 (486 vs 530 pg/mL). Treatment with oral or intravenous iron was much more frequent in anemic patients (31.6% vs 9.9%; P < .001). The logistic regression analysis of factors associated with anemia revealed that renal function and the use of angiotensin-converting enzyme (ACE) inhibitors were significant but not the degree of iron deficiency. In conclusion, iron deficiency in renal transplant patients with chronic nephropathy is frequent and insufficiently treated. Although it may be an aggravating factor, it was not shown to be a determining factor for the presence or absence of anemia in the patients as a group.     

Assessment of iron status by erythrocyte ferritin in uremic patients with or without recombinant human erythropoietin therapy.

Erythrocyte ferritin may be a better estimator of iron bioavailability than the conventional markers of iron stores (serum ferritin and transferrin saturation). To investigate the accuracy of these conventional markers in uremic patients compared with erythrocyte ferritin, we studied 29 chronic hemodialysis patients on erythropoietin (EPO) therapy, 18 without EPO therapy, and 22 healthy control subjects. Apart from the red blood cell indices, serum ferritin, transferrin saturation, and erythrocyte ferritin, the analytical study included red blood cell protoporphyrin and plasma aluminum levels. The control group showed erythrocyte ferritin concentrations between 8.3 and 12.5 attograms/cell (95% confidence interval). In the EPO group, red blood cell protoporphyrin correlated negatively with erythrocyte ferritin, but not with serum ferritin or transferrin saturation. In the non-EPO group, serum ferritin, erythrocyte ferritin, and transferrin saturation did not correlate with red blood cell protoporphyrin. Even though erythrocyte ferritin correlated well with serum ferritin in the EPO group (r = 0.61, P = 0.0003), the sensitivity of normal serum ferritin levels (30 to 300 ng/mL) to discard a low erythrocyte ferritin concentration (erythrocyte ferritin less than 7 ag/cell) was 0.53, while the sensitivity of serum ferritin at levels less than 30 ng/mL to indicate an absolute iron deficiency expressed as a low erythrocyte ferritin concentration was 0.28. Only values of serum ferritin and transferrin saturation greater than 300 ng/mL and 35%, respectively, could rule out a relative iron deficiency expressed as a low erythrocyte ferritin and high red blood cell protoporphyrin concentration. Plasma aluminum levels did not correlate with red blood cell protoporphyrin or erythrocyte ferritin levels in either uremic group.(ABSTRACT TRUNCATED AT 250 WORDS)     

A prospective crossover trial comparing intermittent intravenous and continuous oral iron supplements in peritoneal dialysis patients.

BACKGROUND: Concomitant iron supplementation is required in the great majority of erythropoietin (Epo)-treated patients with end-stage renal failure. Intravenous (i.v.) iron supplementation has been demonstrated to be superior to oral iron therapy in Epo-treated haemodialysis patients, but comparative data in iron-replete peritoneal dialysis (PD) patients are lacking. METHODS: A 12-month, prospective, crossover trial comparing oral and i.v. iron supplementation was conducted in all Princess Alexandra Hospital PD patients who were on a stable dose of Epo, had no identifiable cause of impaired haemopoiesis other than uraemia, and had normal iron stores (transferrin saturation >20% and serum ferritin 100-500 mg/l). Patients received daily oral iron supplements (210 mg elemental iron per day) for 4 months followed by intermittent, outpatient i.v. iron infusions (200 mg every 2 months) for 4 months, followed by a further 4 months of oral iron. Haemoglobin levels and body iron stores were measured monthly. RESULTS: Twenty-eight individuals were entered into the study and 16 patients completed 12 months of follow-up. Using repeated-measures analysis of variance, haemoglobin concentrations increased significantly during the i.v. phase (108+/-3 to 114+/-3 g/l) compared with each of the oral phases (109+/-3 to 108+/-3 g/l and 114+/-3 to 107+/-4 g/l, P<0.05). Similar patterns were seen for both percentage transferrin saturation (23.8+/-2.3 to 30.8+/-3.0%, 24.8+/-2.1 to 23.8+/-2.3%, and 30.8+/-3.0 to 26.8+/-2.1%, respectively, P<0.05) and ferritin (385+/-47 to 544+/-103 mg/l, 317+/-46 to 385+/-47 mg/l, 544+/-103 to 463+/-50 mg/l, respectively, P=0.10). No significant changes in Epo dosages were observed throughout the study. I.v. iron supplementation was associated with a much lower incidence of gastrointestinal disturbances (11 vs 46%, P<0.05), but exceeded the cost of oral iron treatment by 6.5-fold. CONCLUSIONS: Two-monthly i.v. iron infusions represent a practical alternative to oral iron and can be safely administered to PD patients in an outpatient setting. Compared with daily oral therapy, 2-monthly i.v. iron supplementation in PD patients was better tolerated and resulted in superior haemoglobin levels and body iron stores.     

Soluble transferrin receptor is correlated with erythropoietin sensitivity in dialysis patients.

BACKGROUND: Iron deficiency is the most common cause of erythropoietin (EPO) resistance in dialyzed patients with renal anemia. Subclinical or functional iron deficiency is difficult to diagnose in these patients. The soluble transferrin receptor (sTf-R) is considered as a sensitive and specific indicator of bone marrow iron availability. PATIENTS AND METHODS: To evaluate the clinical usefulness of this novel marker, we investigated relationships between EPO requirements and various hematological and biochemical parameters of erythropoiesis in 27 pediatric end-stage renal failure patients treated by hemodialysis (HD, n = 11) or chronic peritoneal dialysis (PD, n = 16). Iron was substituted intravenously once or twice per week in HD, and by daily oral administration to PD patients. Serum sTf-R concentrations were measured by an enzyme-linked immunosorbent assay. Serum ferritin and transferrin concentrations were determined using nephelometric assays. Hemoglobin and iron levels were estimated by automated procedures. RESULTS: While neither transferrin saturation nor serum ferritin concentrations were indicative of EPO requirements, a highly significant correlation between the EPO efficacy index (EPO dose divided by hemoglobin concentration) and sTf-R was observed (r = 0.65, p = 0.001). The intravenous iron substitution in HD patients was associated with higher ferritin concentrations compared to the orally substituted PD patients (280+/-100 ng/ml vs. 124+/-83 ng/ml, p<0.002). In contrast, sTf-R concentrations were similar in both treatment groups (25.7+/-7.7 nM vs. 27+/-10.8 nM, n.s.), as were hemoglobin concentrations and EPO requirements. CONCLUSION: Our results suggest that sTf-R is a more sensitive indicator of functional iron deficiency and impaired EPO responsiveness than serum ferritin or transferrin saturation in dialyzed patients. Intensified iron substitution to patients with elevated sTf-R concentrations may considerably improve the cost efficacy of EPO treatment.     

Effect of an intravenous iron dextran regimen on iron stores, hemoglobin, and erythropoietin requirements in hemodialysis patients

Iron deficiency is a common cause of delayed or diminished response to erythropoietin (EPO) in hemodialysis patients. Although oral iron is often prescribed to replete iron stores, this approach to iron supplementation may not be adequate with chronic EPO therapy. Intravenous (IV) iron dextran may be an effective alternative approach to replete iron stores and may facilitate more cost-effective use of EPO. The purpose of this study was to evaluate an IV iron dextran regimen that consisted of a loading dose phase followed by monthly maintenance doses of iron dextran. The effect of this regimen on iron stores, hemoglobin, and EPO doses was evaluated. This was an open prospective study in adult hemodialysis patients who were iron deficient as defined by a serum ferritin less than 100 ng/mL or transferrin saturation (TSAT) of less than 20%. Patients were loaded with 1 g iron dextran in five divided doses and then received monthly maintenance doses of 100 mg for the 4-month study period. Values of serum ferritin, TSAT, hemoglobin, and EPO dose were followed for the 4-month study period. Thirty hemodialysis patients receiving EPO were identified as being iron deficient and were enrolled in the study. The mean serum ferritin increased significantly from 49 ng/mL at baseline to 225 ng/mL at the end of the study period (P < 0.0001). Mean TSAT also increased significantly from 27% to 33% (P = 0.002). Values for hemoglobin did not change significantly during the study period; however, there was a significant reduction in EPO dose from a mean baseline dose of 112 U/kg/wk to 88 U/kg/wk at the end of the study period (P = 0.009). Seventeen patients experienced an increase in hemoglobin or a decrease in EPO dose. Economic analysis showed that approximately $580 (Cdn) per patient per year could be saved by use of IV iron dextran. The administration of the IV iron dextran regimen in the iron-deficient hemodialysis population was effective at repleting and maintaining iron stores and reducing EPO use.     

Comparison of parenteral iron sucrose and ferric chloride during erythropoietin therapy of haemodialysis patients

Aim:   To compare the effects of i.v. iron sucrose and Fe chloride on the iron indices of haemodialysis patients with anaemia.
Methods:   One hundred and eight haemodialysis patients receiving recombinant human erythropoiesis-stimulating agent (ESA) (mean age 59.37 years) were enrolled and randomly assigned to an iron sucrose or an Fe chloride group. Iron supplements were administered at 100 mg/week during the first 4 weeks (loading dose). Ferritin and transferrin saturation (TSAT) were then measured and dose adjusted. Ninety-eight subjects completed treatment; 51 in the iron sucrose group and 47 in the Fe chloride group. Ferritin, TSAT, haematocrit (Hct), reticulocyte count, serum albumin, fractional clearance of urea (Kt/V) and intact parathyroid hormone (iPTH) were measured.
Results:   There was no significant difference in baseline characteristics between the groups. Significant differences between the groups were observed in both iron indices and ESA dosage. Hct at week 24 (31.1% vs 29.7%, P  = 0.006) and ferritin at week 20 (731.3 vs 631.7 ng/mL, P  = 0.006) in the iron sucrose group were significantly higher than in the Fe chloride group. ESA dosage used in the iron sucrose group at week 8 was significantly lower than in the Fe chloride group (244.9 vs 322.6 U/kg per month, P  = 0.003), and iron sucrose group received significantly lower iron dose than the Fe chloride group at week 8 ( P  = 0.005).
Conclusion:   Although the differences in ESA dosage, ferritin and iron dosage between two groups were found during the study period while similar results were shown at the end of 24 week study. Thus, iron sucrose and Fe chloride are safe and work equally well for haemodialysis patients.     

Soluble transferrin receptors and reticulocyte hemoglobin concentration in the assessment of iron deficiency in hemodialysis patients

BACKGROUND: Diagnosing iron deficiency in hemodialysis (HD) patients is crucial for correct anemia management. Hypochromic erythrocytes appear to be the best available marker, but they are often unavailable. Transferrin saturation (TSAT) and ferritin are also indicated as reference markers by guidelines. We evaluated the usefulness of soluble transferrin receptor (s-TfR) and reticulocyte hemoglobin concentration (CHr), which have been recently proposed as more sensitive functional iron deficiency indicators. METHODS: A single-center unselected cohort of 39 chronic HD patients underwent a cross-sectional determination of hemoglobin (Hb), hematocrit (Hct), CHr, transferrin, iron, TSAT, ferritin, folate, vitamin B12 and s-TfR. Twenty-nine patients (74.4%) were treated with subcutaneous erythropoietin (EPO) at a dose of 122 +/- 98 U/kg/week and 24 patients (61.5%) were treated with intravenous (i.v.) iron gluconate, 62.5 mg/week. RESULTS: Hb was 11.1 +/- 1.2 g/dL, Hct 34.4 +/- 3.7%, CHr 32.7 +/- 3.8 pg, transferrin 170 +/- 31 mg/dL, iron 60.2 +/- 25.9 mg/dL, TSAT 30 +/- 18%; ferritin 204 +/- 219 ng/mL, folate 4.2 +/- 1.0 mcg/L, vitamin B12 0.58 +/- 0.15 mcg/L, and s-TfR 1.94 +/- 0.83 mg/L. Both TSAT and s-TfR significantly correlated with CHr, but no relationship could be found between s-TfR and TSAT or between s-TfR and ferritin. Dividing the population into two groups based on iron repletion (ferritin >100 ng/mL and TSAT >20%) we found no differences for CHr levels and significantly lower levels of s-TfR in the replete group (s-TfR 1.71 +/- 0.70 vs. 2.29 +/- 0.90 mg/L; p=0.033). Analysis of 2x2 tables demonstrated that 44% of patients with TSAT >20% had elevated (>1.5 mg/L) s-TfR, indicating a possible functional iron deficiency, but covariance analysis showed that TSAT had a better correlation to CHr. CONCLUSIONS: No clear-cut advantages in the use of CHr content and s-TfR levels as single diagnostic tests could be demonstrated by this cross-sectional study. However, our results suggest that the combined use of TSAT <20% and s-TfR >1.5 mg/L (therefore, including all patients with low TSAT, but also patients with high s-TfR despite normal TSAT) could improve functional iron deficiency detection in dialysis patients suspected of having inflammatory conditions.     

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.     

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      

Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients.

BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22). CONCLUSIONS: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.     

Role of C-reactive protein, reticulocyte haemoglobin content and inflammatory markers in iron and erythropoietin administration in dialysis patients

AIM: C-reactive protein (CRP) is an acute phase reactant protein, which becomes elevated in response to inflammation, infections or malignancies. These conditions are well known causes of bone marrow hyporesponsiveness and erythropoietin resistance in dialysis patients. The role of iron-deficiency as a cause of hyporesponsiveness under these conditions is not clear. Reticulocyte haemoglobin content (CHr) is one of several iron indices used to determine iron deficiency in dialysis patients. The aim of this study is to evaluate the role of CRP and CHr in iron administration and anaemia management in dialysis patients. METHODS: In 47 haemodialysis patients with ferritin levels of >500 ng/mL, CRP, CHr, transferrin saturation (TSAT), other markers and erythropoietin dose were evaluated. Patients with CRP < 5 mg/L (Group A) were compared to patients with CRP > 5 mg/L (Group B). RESULTS: Ferritin levels in the two groups were not different. Weekly erythropoietin was significantly different between the two groups. Group B required an average of 121% more erythropoietin than Group A to maintain similar haemoglobin levels of 11-12 g/dL 36% of Group B had CHr < 29 pg versus 7% of patients in Group A. 39% of patients in Group B also had TSAT < 20% versus 0% in Group A. Group A also had more arteriovenous (AV) fistulae as dialysis access than group B. CONCLUSION: Data indicate that low CHr, similar to low TSAT, could be associated with inflammatory process and erythropoietin resistance, but not necessarily with iron-deficiency. High CRP association with low CHr and low TSAT levels can explain the lack of response to further IV iron therapy. AV grafts, contrary to AV fistulae, are associated with high inflammatory markers and also with a higher erythropoietin requirement.     

A randomized trial of iron deficiency testing strategies in hemodialysis patients.

BACKGROUND: Diagnosis of iron deficiency in hemodialysis patients is limited by the inaccuracy of commonly used tests. Reticulocyte hemoglobin content (CHr) is a test that has shown promise for improved diagnosis in preliminary studies. The purpose of this study was to compare iron management guided by serum ferritin and transferrin saturation to management guided by CHr. METHODS: A total of 157 hemodialysis patients from three centers were randomized to iron management based on (group 1) serum ferritin and transferrin saturation, or (group 2) CHr. Patients were followed for six months. Treatment with intravenous iron dextran, 100 mg for 10 consecutive treatments was initiated if (group 1) serum ferritin <100 ng/mL or transferrin saturation <20%, or (group 2) CHr <29 pg. RESULTS: There was no significant difference between groups in the final mean hematocrit or epoetin dose. The mean weekly dose of iron dextran was 47.7 +/- 35.5 mg in group 1 compared to 22.9 +/- 20.5 mg in group 2 (P = 0.02). The final mean serum ferritin was 399.5 +/- 247.6 ng/mL in group 1 compared to 304.7 +/- 290.6 ng/mL in group 2 (P < 0.05). There was no significant difference in final TSAT or CHr. Coefficient of variation was significantly lower for CHr than serum ferritin and transferrin saturation (3.4% vs. 43.6% and 39.5%, respectively). CONCLUSIONS: CHr is a markedly more stable analyte than serum ferritin or transferrin saturation, and iron management based on CHr results in similar hematocrit and epoetin dosing while significantly reducing IV iron exposure.     

A randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rHuEpo.

BACKGROUND: The objectives of the present trial were to compare the efficacy and safety of two i.v. iron preparations with respect to haemoglobin levels, iron status and recombinant human erythropoetin (rHuEpo) dosage requirements in stable, rHuEpo-treated haemodialysis patients (maintenance phase of iron treatment) over 6 months. METHODS: A total of 59 patients were randomized and assigned to one of two treatment groups and 55 patients were analysed (iron sucrose n=27; iron gluconate n=28). Iron sucrose was administered in a dose of 250 mg iron diluted in 100 ml normal saline given over 60 min once per month, while 62.5 mg iron as iron gluconate was given once per week in a slow push injection (5 min). RESULTS: --Efficacy parameters: Haemoglobin levels could be maintained from baseline to endpoint in both groups. There were, however, more patients in the iron sucrose group than in the iron gluconate group for whom treatment was discontinued because their haemoglobin values exceeded 12.5 g/dl or ferritin values exceeded 1000 ng/ml (five vs two and three vs one patient, respectively). Transferrin saturation and serum ferritin increased significantly in both groups (+255.7 ng/ml with iron sucrose and +278.5 ng/ml with iron gluconate), while rHuEpo dosage did not change significantly throughout the study. --Safety parameters: There were a total of 174 infusions of iron sucrose and 720 injections of iron gluconate during the trial; all of them were well tolerated. In particular, we did not observe anaphylactoid reactions or any events suggestive of iron toxicity such as hypotension, dizziness, or nausea. CONCLUSIONS: High doses of iron sucrose (Venofer((R)) at a dose of 250 mg/month) was equally effective in maintaining haemoglobin and equally well tolerated as low doses of iron gluconate (Ferrlecit((R)) at a dose of 62.5 mg once per week) in stable, rHuEpo treated haemodialysis patients.     

Beneficial Hematologic Effects of Daily Oral Ascorbic Acid Therapy in ESRD Patients with Anemia and Abnormal Iron Homeostasis: A Preliminary Study

Aim. To determine the efficacy and effects of the oral administration of ascorbic acid on anemia management in ESRD patients with hyperferritinemia. Methods. Twenty-one anemic hemodialysis patients with ferritin levels greater than 350 ng/mL had received oral daily ascorbic acid at a dose of 500 mg/day and were retrospectively studied. Hemoglobin, hematocrit, EPO dose, ferritin, and transferrin saturation were recorded at baseline and after three months of treatment. EPO dose/hematocrit was calculated. Serum oxalate levels were also measured. Results. Hb increased 9% from 11.4 to 12.2 gm/dL (p = 0.05), HCT increased 10% from 33.3 to 36.7% (p = 0.05), but EPO dose requirement decreased 33% from 26,229 to 17,559 U/week (p = 0.03). Ferritin levels decreased 21% from 873 to 691 ng/mL (p = 0.004). Mean oxalate level during therapy was 87 umol/L (normal <27). Patients with oxalate levels >27 umol/L were instructed to stop ascorbic acid treatment, and mean levels decreased from 107 to 19 umol/L (p = 0.01) over a mean time of 71 days. Conclusion. In this study, daily oral ascorbic therapy decreased ferritin levels and EPO dose requirements while raising hemoglobin and hematocrit level. This beneficial profile of effects of ascorbic acid therapy is consistent with improvement of EPO resistance and cost savings in this population.     

Characteristics of Anemia and Iron Deficiency After Kidney Transplant

BackgroundNumerous studies have shown that iron deficiency is common in patients with end-stage renal disease. However, change of iron deficiency after kidney transplant (KT) is not fully understood. This study was undertaken to examine sequential changes of iron level after KT.MethodsA total of 1080 KT recipients enrolled in a multicenter observational cohort study between July 2012 and August 2018. A total of 786 patients with transferrin saturation and ferritin level at pretransplant and 1 year after KT were reviewed. Iron deficiency was defined as ferritin <200 ng/mL and total saturation of transferrin (TSAT) < 20%. Anemia was defined as hemoglobin (Hb) < 13 g/dL (male) or <12 g/dL (female).ResultsHemoglobin at 1 year after KT was higher than Hb at KT (13.64 [SD, 1.87] g/dL vs 10.53 [SD, 1.63] g/dL; P < .001). The TSAT decreased from baseline at 1 year after KT (33.89% [SD, 18.73%] vs 29.09% [SD, 14.54%]; P < .001), and ferritin level decreased from baseline at 1 year (190.63 [SD, 217.43] ng/mL vs 141.39 [194.25] ng/mL; P < .001). In patients with anemia at pretransplant, the group with anemia at 1 year after KT (persistent group) and the group without anemia at 1 year after KT (improved group) were compared. The persistent group showed higher pretransplant TSAT, lower 1-year TSAT, and lower estimated glomerular filtration rate at 1 year after KT than the improved group. In multivariate analysis, low ferritin at KT, low TSAT at 1 year, and high ferritin at 1 year were the risk factors for low Hb level at 1 year after adjusting multiple variables.ConclusionAnemia improved within 1 year after KT, although patients with iron deficiency increased. While ferritin reflected the inflammatory status, low TSAT at 1 year after KT was a risk factor for anemia at 1 year after KT.