Profiling hemodialysis patients with high ferritin levels

AIMS: Hemodialysis patients receiving intravenous iron and erythropoietin may develop greatly elevated ferritin levels. Both iron overload and inflammation may account for this hyperferritinemia. The aim of this study was to try to identify the cause of the high ferritin level among individual patients. METHODS: Sixty-seven chronic hemodialysis patients with ferritn levels < 700 microg/l were compared to 47 patients whose ferritin levels were > or = 700 microg/l. Clinical and laboratory data were collected and evaluated by cluster analysis which allowed patients to be placed into statistically dissimilar groups. RESULTS: The 47 high ferritin patients segregated into 3 clusters consisting of 28, 3, and 16 patients based on ferritin, zinc protoporphyrin, albumin, C-reactive protein, and hemoglobin. When contrasted with cluster 1, cluster 3 patients had higher levels of Zn-PP, CRP, and ferritin and lower levels of albumin and hemoglobin. CONCLUSIONS: Utilizing these data and the results of many other studies, we conclude that, relative to cluster 1, cluster 3 patients had a more intense inflammatory response that blocked iron mobilization required for erythrocyte production. Cluster analysis appears to be a useful method of analyzing clinical data of relatively small patient population.     

Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients

Iron deficiency limits the efficacy of recombinant human erythropoietin (rhEPO) therapy in end-stage renal disease (ESRD) patients. Functional iron deficiency occurs with serum ferritin >500 ng/ml and/or transferrin saturation (TSAT) of 20 to 30%. This study examines the effects of a maintenance intravenous iron dextran (ivID) protocol that increased TSAT in ESRD hemodialysis patients from conventional levels of 20 to 30% (control group) to those of 30 to 50% (study group) for a period of 6 mo. Forty-two patients receiving chronic hemodialysis completed a 16- to 20-wk run-in period, during which maintenance ivID and rhEPO were administered in amounts to achieve average TSAT of 20 to 30% and baseline levels of hemoglobin of 9.5 to 12.0 g/dl. After the run-in period, 19 patients randomized to the control group received ivID doses of 25 to 150 mg/wk for 6 mo. Twenty-three patients randomized to the study group received four to six loading doses of ivID, 100 mg each, over a 2-wk period to achieve a TSAT >30% followed by 25 to 150 mg weekly to maintain TSAT between 30 and 50% for 6 mo. Both regimens were effective in maintaining targeted hemoglobin levels. Fifteen patients in the control group and 17 patients in the study group finished the study in which the primary outcome parameter by intention to treat analysis was the rhEPO dose needed to maintain prestudy hemoglobin levels. Maintenance ivID requirements in the study group increased from 176 to 501 mg/mo and were associated with a progressive increase in serum ferritin to 658 ng/ml. Epoetin dose requirements for the study group decreased by the third month and remained 40% lower than for the control group, resulting in an overall cost savings in managing the anemia. Secondary indicators of iron-deficient erythropoiesis were also assessed. Zinc protoporphyrin did not change in either group. Reticulocyte hemoglobin content increased only in the study group from 28.5 to 30.1 pg. It is concluded that maintenance of TSAT between 30 and 50% reduces rhEPO requirements significantly over a 6-mo period.     

Varying intervals of subcutaneous epoetin alfa in hemodialysis patients

BACKGROUND: The optimal subcutaneous (SC) epoetin alfa strategy is unestablished. The individual variability in dose requirements needs consideration. In this study, prolonged intervals were assessed in relation to varying dose requirements. METHODS: The study included 153 hemodialysis (HD) patients on stable SC epoetin alfa. Based on dose requirements, the patients received either 4,000 U (group I, n=51) or 10,000 U (group II, n=102) as whole 1 mL vials at prolonged intervals. The study comprised three 8-week periods: an initial period maintaining the basal regimens, an adjustment period where the intervals were prolonged, and a maintenance period. Alterations in hemoglobin (Hb), weekly doses and intervals in each group were compared. RESULTS: One hundred and thirty-seven patients completed the study (48 in group I and 89 in group II). In group I, the mean interval was prolonged from 5.4 +/- 1.9 to 7.8 +/- 3.1 days (p=0,01) with stable Hb and EPO doses. In group II, prolonged intervals were associated with a reduction in mean Hb below target level and a significant increase in EPO doses (p=0,002). Iron deficiency and inflammation could explain the poor response in approximately one-third of the patients. CONCLUSIONS: In HD patients, the optimal injection frequency should be individually adjusted. Prolonged intervals can be applied to patients with low-dose requirements. Observing iron status and inflammation is necessary for optimal response.     

Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study

Few data exist to guide treatment of anemic hemodialysis patients with high ferritin and low transferrin saturation (TSAT). The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial was designed to evaluate the efficacy of intravenous ferric gluconate in such patients. Inclusion criteria were hemoglobin or=225 IU/kg per wk or >or=22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n=134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P=0.028) in the intravenous iron group (1.6 +/- 1.3 g/dl) than in the control group (1.1 +/- 1.4 g/dl). Hemoglobin response occurred faster (P=0.035) and more patients responded after intravenous iron than in the control group (P=0.041). Ferritin 800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (-174 +/- 225 ng/ml) and increased after intravenous iron (173 +/- 272 ng/ml; P<0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 +/- 7.4 versus 1.8 +/- 5.2%; P<0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT 相似文献   

Comparison of the therapeutic efficacy of epoetin beta and epoetin alfa in maintenance phase hemodialysis patients

In May 2009 for financial reasons, the epoetin product used for hemoglobin (Hb) maintenance in our renal dialysis unit was changed from epoetin beta to epoetin alfa. Although widely believed that the dosage requirements are the same, we undertook a retrospective analysis to investigate whether the dosage requirements in chronic renal failure patients were comparable for both preparations. We studied 128 stable end-stage renal failure patients on hemodialysis (three times per week) receiving erythropoietin therapy to maintain their Hb at 11-12.5 g/dL. Patients were excluded if within the study period they developed signs of infection, bleeding, required blood transfusion, were under-dialyzed, or required hospital admission. Regular monthly Hb concentrations and hematocrit (Hct) levels were measured for each patient. The weekly EPO index (defined as weekly epoetin dose/mean monthly Hct) was derived for each patient, before and after regime change. Of the 128 patients in end-stage renal failure, 79 were included in the study. There was no significant difference between the two preparations in terms of Hct level achieved (p = 0.15). However, the median weekly epoetin dose requirement increased from 6733 (range 750-30,000) IU/week to 9000 (250-30,667) IU/week (p < 0.001). EPO index similarly increased from 20,465 (2500-130,846) IU/week/% to 27,073 (729-98,937) IU/week/% (p < 0.001). Our study showed that a higher dose of epoetin alfa was needed to maintain target Hb concentration.     

Erythrocyte ferritin in patients on chronic hemodialysis treatment

Serum ferritin (SF) and erythrocyte ferritin (EF) were evaluated in 35 patients on chronic hemodialysis treatment (CHD), in 45 healthy subjects and in 22 nonnephropathic females with iron deficiency anemia. Twenty-five CHD patients with basal SF less than 500 micrograms/l were treated orally with 200 mg of Fe2+ for 2 months and the positive (hemoglobin increase greater than 1 g/dl) or negative response to the therapy was correlated to the basal levels of SF and EF. Three groups of CHD patients could be defined on the basis of their basal SF levels (hypo-, normo- or hyperferritinemic). Nine patients with increased SF levels had also EF levels significantly higher than the other CHD patients and controls since they were probably iron-overloaded. In the other 2 groups of CHD patients, EF levels were significantly higher than in controls for each level of SF probably because of the reduced utilization of iron by uremic bone marrow. Among the 25 treated CHD patients, only 5 responded to the therapy: 3 were hypoferritinemic while the other 2 responders had basal SF within the normal range. Four hypoferritinemic patients did not respond to the therapy. Four out of five responders had the lowest EF levels among CHD patients. EF measurement could be an important and useful test in detecting the presence of an iron deficiency erythropoiesis in CHD patients.     

HLA antigens and serum ferritin in hemodialysis patients

The evolution of serum ferritin levels in 111 chronic-hemodialysis patients is prospectively studied. Patients were classified in two groups according to the presence or absence of 'hemochromatosis antigens' (HLA A3, B7 or B14) in their HLA typing. Levels of serum ferritin were similar in both groups before they started dialysis and during the first year. On the contrary, in the second and third hemodialysis years serum ferritin was higher in the group carrying 'hemochromatosis antigens'. These differences were observed in patients treated with parenteral iron either in the form of transfusions or as intravenous dextran-iron but not in patients receiving oral iron. We conclude that the risk of developing iron overload is greater in hemodialysis patients with HLA A3, B7 or B14. Nevertheless, this potential risk can be minimized with a restrictive policy on the use of parenteral iron (transfusions, intravenous dextran-iron).     

Reduced hemodialysis adequacy after hemoglobin normalization with epoetin

BACKGROUND: Increased hemoglobin (Hb) levels and higher blood viscosity could reduce hemodialyzer clearance. We examined hemodialysis (HD) adequacy after treatment with epoetin alfa aimed at normalizing Hb levels. METHODS: Thirty-three HD patients were randomly allocated to achieve a normal Hb level (135-160 g/L) or a subnormal (control) Hb level of 90-120 g/L. HD adequacy was assessed by Kt/V measurement. RESULTS: In the 24 evaluable patients, Hb levels reached 144 +/- 11 g/L in the normal Hb group (n=10) and 109 +/- 10 g/L in the subnormal group (n=14). Single-pool Kt/V decreased from 1.25 +/- 0.19 to 1.15 +/- 0.13 (p<0.01) in the normal Hb group, but remained constant in the subnormal group (1.26 +/- 0.26 and 1.26 +/- 0.28). CONCLUSIONS: Normalization of Hb with epoetin alfa in HD patients resulted in a slight but statistically significant reduction in Kt/V. Therefore, when Hb is normalized, an increased dialysis dose could be necessary to maintain dialysis adequacy.     

Diagnostic value of iron indices in hemodialysis patients receiving epoetin.

BACKGROUND: Iron deficiency remains a common cause of hyporesponsiveness to epoetin in hemodialysis patients. However, considerable controversy exists regarding the best strategies for diagnosis and treatment. METHODS: As part of a multicenter randomized clinical trial of intravenous versus subcutaneous administration of epoetin, we made monthly determinations of serum iron, total iron binding capacity, percentage transferrin saturation, and serum ferritin. If a patient had serum ferritin <100 ng/mL or the combination of serum ferritin <400 ng/mL and a transferrin saturation <20%, he/she received parenteral iron, given as iron dextran 100 mg at ten consecutive dialysis sessions. We analyzed parenteral iron use during the trial, the effect of its administration on iron indices and epoetin dose, and the ability of the iron indices to predict a reduction in epoetin dose in response to parenteral iron administration. RESULTS: Eighty-seven percent of the 208 patients required parenteral iron to maintain adequate iron stores at an average dose of 1516 mg over 41.7 weeks, or 36 mg/week. Only two of 180 patients experienced serious reactions to intravenous iron administration. Two thirds of the patients receiving parenteral iron had a decrease in their epoetin requirement of at least 30 U/kg/week compared with 29% of patients who did not receive iron (P = 0.004). The average dose decrease 12 weeks after initiating iron therapy was 1763 U/week. A serum ferritin <200 ng/mL had the best positive predictive value (76%) for predicting a response to parenteral iron administration, but it still had limited clinical utility. CONCLUSIONS: Iron deficiency commonly develops during epoetin therapy, and parenteral iron administration may result in a clinically significant reduction in epoetin dose. The use of transferrin saturation or serum ferritin as an indicator for parenteral iron administration has limited utility.     

Intravenous iron gluconate administration increases circulating PAPP-A in hemodialysis patients

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a proatherosclerotic molecule, interrelated with oxidative stress in hemodialysis (HD) patients. As intravenous (IV) iron might enhance oxidative stress in HD patients, this study investigates circulating PAPP-A during HD session and after IV iron administration. METHODS: In 20 HD patients, plasma PAPP-A concentration was assessed immunochemically during 2 HD sessions (prior to HD and at 60, 130, and 240 min of HD session). Sodium ferric gluconate (62.5 mg) was given IV to all patients 65 min after the start of the second HD. RESULTS: Sixty-five min after IV iron application, there was a significant increase in plasma PAPP-A (from 36.0+/-9.9 to 79.6+/-28.9 mU/L, p<0.0001). At the end of this HD session, PAPP-A decreased significantly (p<0.0001), but still remained 1.5-fold greater compared with predialysis levels (p<0.0005). CONCLUSION: IV iron increases circulating PAPP-A, and in this way, it might contribute to more pronounced cardiovascular complications in HD patients.     

Serum ferritin and hemochromatosis alleles in chronic hemodialysis patients

There have been some reports on the risk of developing hemosiderosis in hemodialysis patients when heavily transfused and simultaneously possessing hemochromatosis alleles (HA). We evaluated 99 patients on chronic hemodialysis estimating their serum ferritin (SF) levels, transfusion rate, and prevalence of HLA A3, B7 and B14 alleles, which are considered to be more frequent in idiopathic hemochromatosis. We analyzed the patients as a whole group and also separately as low or high transfusion groups. There was no correlation between the number of HA and the mean SF levels. The presence of HA is not a risk factor for the development of hemosiderosis when excessive transfusions and parenteral iron administration are avoided.     

Serial ferritin concentrations in hemodialysis patients receiving intravenous iron

BACKGROUND: Treatment of the anemia of chronic renal failure with intravenous iron and erythropoietin is highly effective, but frequently leads to ferritin levels which are much higher than those seen in the general population. High ferritin concentrations raise concern about the potential toxicity of increased body iron stores. PATIENTS AND METHODS: We retrospectively evaluated parameters of iron metabolism over a 4-year period among all our chronic hemodialysis patients who had been receiving intravenous iron and erythropoietin. Initially, patients received intermittent infusions of 300 mg intravenous iron x 3 doses for a low ferritin or low percent saturation of total iron binding capacity (TIBC), but this protocol was subsequently changed to weekly or biweekly infusions of 50-100 mg. RESULTS: We observed an improvement in average hemoglobin values, modest increases in serum iron and saturation of iron binding capacity, and a 125% increase in ferritin levels over 4 years. TIBC decreased. Overall, ferritin values increased 79 microg/l for each 1% increase in TIBC saturation. Ten patients with ferritin concentration greater than 1,000 pg/l received a three month course of vitamin C with no decline in the ferritin concentration. CONCLUSION: Current protocols for iron delivery may result in progressive increases in ferritin levels. Concern about the risks of iron overload should temper the quantity of iron used in dialysis programs.     

Oxidative stress in renal anemia of hemodialysis patients is mitigated by epoetin treatment

BACKGROUND/AIMS: Oxidative stress often occurs in chronic hemodialysis (HD) patients. The objective of our study was to investigate the interrelationship between oxidative stress and the degree of renal anemia. METHODS: In 107 consecutive HD patients, serum concentrations of two major aldehydic lipid peroxidation (LPO) products, 4-hydroxynonenal (HNE) and malondialdehyde (MDA), and of protein carbonyls were analyzed as parameters of oxidative stress and related to the degree of renal anemia. Additionally, in 76 patients treated with epoetin long-term changes in the serum levels of aldehydic LPO products were observed. RESULTS: In HD patients, serum levels of HNE, MDA, and protein carbonyls are increased in comparison to controls. The lower the hemoglobin, i.e. the stronger the degree of renal anemia, the higher the serum concentrations of HNE, MDA, and protein carbonyls. The HNE and MDA levels decreased during HD. Long-term studies on the correction of renal anemia by epoetin demonstrated a mitigation of oxidative stress during this therapy. During periods of 1 and 2 years, it was observed that the serum levels of HNE and MDA could be reduced. CONCLUSION: Chronic renal failure is connected with oxidative stress which correlates with the degree of renal anemia, and the serum levels of aldehydic LPO products could be reduced during correction of renal anemia by epoetin.     

Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain

Purpose

Ketamine has been administered epidurally and intrathecally for operative and post-operative pain control. Animal studies showed potentiation of analgesia induced by ketamine and morphine. We hypothesized that intrathecal ketamine would potentiate the effects of intrathecal morphine in the treatment of cancer pain.

Methods

A double blind, cross over study was designed to evaluate the effect of ketamine on spinal morphine analgesia in terminal cancer pain patients. A two-phase protocol was used; phase M, intrathecal morphine alone twice daily; phase M+K, co-administration of ketamine (1.0 mg) with morphine intrathecally twice daily. The dose of morphine was titrated upwards until acceptable pain relief was achieved, defined by numeric rating scales (0–10) ≤ 3, and the rescue dose of morphine was less than 5 mg after each intrathecal administration for two days. The dose of intrathecal morphine was defined as the effective dose.

Results

The effective dose of intrathecal morphine in phase M of 0.38 ± 0.04 mg · day^?1 was higher than that in phase M+K (0.17 ± 0.02 mg · day^?1) (P < 0.05). The average pain scales were 7.95 ± 0.25 before intrathecal drug administration. Pain scales were decreased to 2.2 ± 0.17 (P < 0.05) in phase M and 1.95 ± 0.20 (P < 0.05) in phase M+K after the effective dose of morphine had been reached. No serious side effects were observed in this study.

Conclusion

The present study demonstrates that ketamine enhances the analgesic effect of morphine, thus reducing the dose of intrathecal morphine.     

Two-dose epoetin alfa reduces blood transfusions compared with autologous donation

This study evaluated whether patients receiving a two-dose regime of epoetin alfa received less allogeneic blood than patients donating autologous blood before primary hip arthroplasty. Consenting patients with a hemoglobin level between 12 and 15 g/dL were randomly assigned to a two-dose administration of epoetin alfa (19 patients) or autologous donation (21 patients). Sixteen percent of the patients in the epoetin alfa group and 52% of the patients in the autologous donation group received transfusions, with a mean volume of 90 cc per patient in the epoetin alfa group and 340 cc in the autologous donation group. Hemoglobin was similar at screening; however, the epoetin alfa group achieved a higher hemoglobin (14.6 g/dL) than the autologous donation group (12.6 g/dL) before surgery. Hemoglobin remained significantly higher in the epoetin alfa group for 3 days after surgery. Administration of two doses of epoetin alfa provided patients with effective and safe reduction of allogeneic blood transfusions and decreased the necessity and difficulty of autologous donation before total hip arthroplasty.     

Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients

Hepcidin is a key regulator of iron metabolism. In this study, we examined whether measurement of hepcidin is useful in assessing recombinant human erythropoietin (rHuEPO) responsiveness in regular hemodialysis (HD) patients in a cross-sectional fashion. We examined the association between serum prohepcidin, a prohormone of hepcidin, and rHuEPO dosage and the rHuEPO/hemoglobin (Hb) ratio in 75 HD patients. We also semiquantatively measured the peak intensity of serum hepcidin-25, the major form of mature hepcidin, in 24 HD patients by using surface-enhanced laser desorption ionization time of flight time mass spectrometry, and compared those between rHuEPO-hyporesponsive (rHuEPO 192 +/- 10 [126-252] IU/kg/week, n = 15) and responsive patients (rHuEPO 40 +/- 9 [0-81] U/kg/week, n = 9). A significant but weak relationship was found between serum prohepcidin and rHuEPO dosage (r = 0.24, p < 0.05) and rHuEPO/Hb ratio (r = 0.22, p = 0.06). However, prohepcidin did not become an indicator of hematopoietic parameters by multiple regression analysis. Serum hepcidin-25 intensity was significantly and positively correlated with ferritin (r = 0.51, p < 0.01) but not with log-transformed C-reactive protein. There was no difference in the intensities of serum hepcidin-25 between rHuEPO-hyporesponsive and responsive patients (64 +/- 10 vs. 52 +/- 16 AU, p = NS). It follows from these findings that the assessment of serum hepcidin using currently available assays was not valid in predicting rHuEPO responsiveness in chronic HD patients.