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.     

Bone marrow failure following severe injury in humans

BACKGROUND: Hematopoietic failure has been observed in experimental animals following shock and injury. In humans, bone marrow dysfunction has been observed in the red cell component and characterized by a persistent anemia, low reticulocyte counts, and the need for repeated transfusions despite adequate iron stores. While a quantitative defect in white blood cell count has not been noted, an alteration in white blood cell function manifesting as an increased susceptibility to infection is well established. Since the etiology of this anemia remains unknown and the bone marrow has been rarely studied following injury, we measured various parameters of hematopoiesis directly using bone marrow from trauma patients and tested the hypothesis that trauma results in profound bone marrow dysfunction, which could explain both the persistent anemia and the alteration in white blood cell function. METHODS: Bone marrow aspirates and peripheral blood were obtained between day 1 and 7 following injury from 45 multiple trauma patients. Normal volunteers served as controls. Peripheral blood was assayed for hemoglobin concentration, reticulocyte count, erythropoietin levels, white blood cell count, and differential. Peripheral blood and bone marrow were cultured for hematopoietic progenitors (CFU-GM, BFU-E, and CFU-E colonies). RESULTS: Bone marrow CFU-GM, BFU-E, and CFU-E colony formation was significantly reduced while peripheral blood CFU-GM, BFU-E, and CFU-E was increased in the trauma patients compared with normal volunteers. Bone marrow stroma failed to grow to confluence by day 14 in >90% of trauma patients. In contrast, bone marrow stroma from volunteers always reached confluence between days 10 and 14 in culture. The mean hemoglobin concentration and reticulocyte counts of the trauma patients were 8.6 +/- 1.0 g/dL and 2.75 +/- 0.7% respectively, while their plasma erythropoietin levels were 2 to 10 times greater than control values. CONCLUSIONS: Release of immature white blood cells into the circulation may also contribute to a failure to clear infection and an increased propensity to organ failure. Concomitantly, profound changes occur within the bone marrow, which include the increased release of erythroid and myeloid progenitors into the circulation, a decrease in progenitor cell growth within the bone marrow, and an impaired growth of the bone marrow stroma. Erythropoietin levels are preserved following trauma, implying that the persistent anemia of injury is related to the failure of the bone marrow to respond to erythropoietin.     

Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation

Treating hemodialysis patients to combat anemia corrects hemoglobin but exacerbates iron deficiency by utilizing iron stores. Patients needing iron should receive this by intravenous (i.v.) means. The Dialysis patients' Response to IV iron with Elevated ferritin (DRIVE) trial investigated the role of i.v. iron in anemic patients with high ferritin, low transferrin saturation, and adequate epoetin doses. We examined whether baseline iron and inflammation markers predict the response of hemoglobin to treatment. Patients (134) were randomized to no added iron or to i.v. ferric gluconate for eight consecutive hemodialysis sessions spanning 6 weeks with epoetin increased by 25% in both groups. The patients started with hemoglobin less than or equal to 11 g/dl, ferritin between 500 and 1200 ng/ml, and transferrin saturation of less than 25%. Significantly, patients with a reticulocyte hemoglobin content greater than or equal to 31.2 pg were over five times more likely to achieve a clinically significant increase in hemoglobin of greater than 2 g/dl. Lower reticulocyte hemoglobin contents did not preclude a response to i.v. iron. Significantly higher transferrin saturation or lower C-reactive protein but not ferritin or soluble transferrin receptor levels predicted a greater response; however their influence was not clinically significant in either group. We conclude that none of the studied markers is a good predictor of response to anemia treatment in this patient sub-population.     

Iron therapy for renal anemia: how much needed,how much harmful?

Iron deficiency is the most common cause of hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in end-stage renal disease (ESRD) patients. Iron deficiency can easily be corrected by intravenous iron administration, which is more effective than oral iron supplementation, at least in adult patients with chronic kidney disease (CKD). Iron status can be monitored by different parameters such as ferritin, transferrin saturation, percentage of hypochromic red blood cells, and/or the reticulocyte hemoglobin content, but an increased erythropoietic response to iron supplementation is the most widely accepted reference standard of iron-deficient erythropoiesis. Parenteral iron therapy is not without acute and chronic adverse events. While provocative animal and in vitro studies suggest induction of inflammation, oxidative stress, and kidney damage by available parenteral iron preparations, several recent clinical studies showed the opposite effects as long as intravenous iron was adequately dosed. Thus, within the recommended international guidelines, parenteral iron administration is safe. Intravenous iron therapy should be withheld during acute infection but not during inflammation. The integration of ESA and intravenous iron therapy into anemia management allowed attainment of target hemoglobin values in the majority of pediatric and adult CKD and ESRD patients.     

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

Purpose

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

Methods

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

Results

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

Conclusions

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

     

Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients

BACKGROUND/AIM: Management of renal anemia in end-stage renal disease requires careful evaluation of the iron status before and in particular during erythropoietin treatment. However, there is no simple and practical iron index accurately predictive of functional iron deficiency in these patients till now. The purpose of this prospective study, therefore, is to evaluate whether a short course of low-dose intravenous iron challenge can detect functional iron deficiency in hemodialysis patients. METHODS: Twenty-four patients with baseline serum ferritin levels between 100 and 500 ng/ml were treated with intravenous saccharated ferric oxide, 960 mg over 24 hemodialysis treatments, and the hemoglobin level was checked every week. RESULTS: Patients whose hemoglobin value increased at least by 1 g/dl within the 8-week period were classified as having functional iron deficiency or as responders (n = 26; 81.2%). All other subjects were classified as having adequate iron levels or as nonresponders (n = 6; 18.8%). There were no significant differences in age, sex, dialysis years, Kt/V, dialyzers, hemoglobin, and basal and final transferrin saturation and ferritin between responders and nonresponders. In addition, there were no iron indices with acceptable levels of sensitivity and specificity. On the contrary, the cutoff value of increments of hemoglobin of at least 0.2 g/dl after a 2-week intravenous iron trial had a sensitivity of 96.2% and a specificity of 100% in all patients (n = 32) and a sensitivity of 100% and a specificity of 100% after patients with transferrin saturation <20% were excluded (n = 24). These values had the greatest utility of the tests studied in this work. CONCLUSION: A 240-mg intravenous iron challenge during a 2-week period may be a simple, accurate, and straightforward method to detect a functional iron deficiency status in hemodialysis patients undergoing erythropoietin therapy.     

The prevalence, course, and characteristics of chronic anemia after heart and lung transplantation.

A retrospective study of the 99 surviving heart and lung transplant (HLT) recipients at one center showed that 31% had significant anemia (hemoglobin less than 100g/L) six months after transplantation. Chronic anemia persisted in 18% of HLT recipients two years posttransplantation. A similar study of 100 heart transplant recipients showed no unexplained anemic patients. The prevalence of anemia after HLT was unrelated to the original diagnosis, immunosuppression, or acute rejection. All HLT recipients appeared to be unduly sensitive to the myelosuppressive effects of azathioprine. Detailed studies in 16 representative patients showed a normochromic, anisocytotic anemia with normal reticulocyte counts, B12 and folate levels, and haptoglobin levels and appropriate erythropoietin levels--but increased ESRs, low/normal iron levels and low/normal total iron binding capacity, normal or raised ferritin levels, and autoantibodies in 4 (25%). Bone marrow aspirates in 10 patients showed dyshemopoiesis out of proportion to the degree of anemia and colonies of activated lymphoid cells. The cause for this anemia appears to be a combination of anemia of chronic disease and dyshemopoiesis, both of uncertain etiology.     

Profile of anemia in children after liver transplantation

BACKGROUND: Clinical and hematological profile of chronic anemia in children after orthotopic liver transplantation (OLT) is unknown. METHODS: We prospectively studied children after orthotopic liver transplantation (OLT) with hemoglobin levels < 2 standard deviation of age appropriate mean for > 6 months. Investigations included hemogram, reticulocyte count, peripheral blood smear, serum vitamin B-12, folic acid levels, iron studies, Coomb's tests, serum erythropoietin (EPO) levels, and stool and urine tests for occult blood. RESULTS: Fifty-six participants (22 male and 34 female, mean age 82.9 months, range 20-232, mean post-OLT duration 48.8 months, range 6-132) were studied. The causes of anemia were idiopathic (32), iron deficiency (4), viral infections (2, HIV=1, parvovirus=1), and lymphoproliferative disease (2). Fifteen participants showed spontaneous recovery within 1-6 months. Thirty-one children with idiopathic anemia had low or normal EPO levels (mean 7.33 mmicro/L, range <2.5 to 15.9, normal 4-24). When outliers (iron deficiency=4, HIV disease= 1) were excluded, there was no statistical correlation between hematocrits and EPO levels. Serum vitamin B-12 levels (n=52) were elevated (normal 110-930 pg/ml) (mean=1,186 pg/ml) in 32 (61.5%) and were significantly higher in those with abnormal liver function tests. CONCLUSION: Anemia is a common problem in children after OLT. More than half the participants had anemia of unknown etiology with an inappropriate EPO response for the degree of anemia. The normal negative correlation between hematocrit and EPO was lost in these children. The observation regarding serum vitamin B-12 levels requires further study.     

The relationship between interferon-gamma and keratinocyte alloantigen expression after burn injury.

BACKGROUND: Cultured keratinocyte (CK) and cadaveric skin allografts have prolonged survival in patients with massive thermal injury. It is unclear if this delayed rejection is due to impaired host responsiveness or decreased graft immunogenicity. Although burn injury has been shown to decrease parameters of allograft response, no studies have examined the effect of burn injury on alloantigen expression. This study investigated the effect of burn size on class II antigen expression in CK allografts as well as on tissue levels of interferon-gamma (IFN-gamma), the principle regulator of alloantigen expression. METHODS: Anesthetized CBA mice (n = 64) received a 0%, 20% partial-thickness (PT), 20% full-thickness (FT), or 40% FT contact burn. Forty-eight hours later, wounds were partially excised and covered with CK allografts from C57BL/6 donors. Five days after burn injury, grafts were analyzed for donor-specific class II antigen. Protein expression was determined by Western immunoblotting and quantified with video densitometry. Wound, serum, and unburned skin levels of IFN-gamma were determined by enzyme-linked immunosorbent assay. Groups were compared by Fisher's analysis of variance. RESULTS: As burn size increased, class II antigen expression decreased (p < 0.001). This corresponded with decreased wound and skin levels of IFN-gamma after 40% burn (p < 0.05); however, wound IFN-gamma was significantly elevated after 20% PT and FT burns (p < 0.01). Serum IFN-gamma increased as burn size increased (p < 0.01). CONCLUSIONS: Burn injury decreases the antigenicity of CK allografts, which partly explains delayed allograft rejection after burn injury. Although wound IFN-gamma increases after minor thermal injury, the profound decrease in wound and skin IFN-gamma after a major burn corresponds with diminished class II antigen expression. The decreased availability of IFN-gamma after major thermal injury provides a mechanism for limited allograft tolerance.     

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

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

Adverse events in chronic hemodialysis patients receiving intravenous iron dextran--a comparison of two products

BACKGROUND: Parenteral iron therapy is required in a majority of chronic dialysis patients who are receiving recombinant human erythropoietin (r-HuEPO) in order to provide adequate iron for erythropoiesis. At this time, there are only two formulations of parenteral iron dextran available for clinical use in the USA. These two preparations of iron dextran have different physical and chemical characteristics that might affect the adverse events experienced by dialysis patients receiving iron dextran. METHODS: We performed a retrospective analysis of all 665 courses of parenteral iron dextran which were administered in our hemodialysis unit from June 1992 through July 1997. An adverse event (AE) was defined as any event which led to interruption of the prescribed course of iron therapy or precluded subsequent administration of parenteral iron in the presence of documented iron deficiency. Database elements included patient age, gender, cause of renal failure, and prior history of drug allergy. The average hemoglobin value and serum iron parameters (iron, total iron binding capacity (TIBC), percent saturation of TIBC, and ferritin) were recorded both pre- and post-iron administration, when available. A course of parenteral iron dextran consisted of a 25-mg test dose, followed by four or five doses of 300 mg each. Iron dextran was infused into the venous limb of the hemodialysis blood circuit over the last 30-60 min of a dialysis treatment. The two forms of iron dextran were designated as Iron A (molecular weight = 165,000) and Iron B (molecular weight = 267,000). RESULTS: Fifty-seven percent of our patients were male, 92% were of white race, and diabetes was the most common cause of renal failure (34%). Sixty-four percent of the patients were 60 years of age or older, and 39% had a history of allergy to one or more drugs. We observed 33 AEs during the administration of parenteral iron dextran, and these AEs occurred in 21 courses of parenteral iron dextran administration. Eighteen of the AEs were gastrointestinal in nature; 7 AEs were cutaneous in nature, 6 AEs had systemic manifestations, while only 2 AEs caused respiratory problems. Two of the AEs were felt to be anaphylactoid in nature. Female gender (p = 0.06) and iron dextran product (p = 0.02) were identified as potential risk factors for the development of an AE. There were 468 courses of Iron A administered, 10 of these courses were complicated by 15 AEs (one or more AE per course). One hundred and ninety-seven courses of Iron B were administered and 11 (5.6%) courses were complicated by the development of 18 AEs (9.1 AEs per 100 courses). Serum iron rose by 22 microg/dl and TIBC saturation increased by 14% after the administration of parenteral iron. The average serum ferritin level rose by 430 microg/l and hemoglobin values rose by an average of 0.8 g/dl. There were no significant differences in the changes of iron parameters or hemoglobin levels between the two iron dextran preparations. CONCLUSIONS: The administration of parenteral iron dextran to chronic hemodialysis patients has a relatively high degree of safety. Both iron products were equally efficacious in increasing serum iron parameters and hemoglobin levels. Even when corrected for other factors, there was a significant difference in the observed AEs between the two formulations of parenteral iron dextran. Our observations, if true, may have important implications for the management of anemia in chronic hemodialysis patients. If a significant number of AEs prohibit the administration of a specific iron dextran product to a large number of chronic hemodialysis patients, then anemia management may become suboptimal. In the future, newer iron products may provide even safer alternatives for the administration of parenteral iron to chronic hemodialysis patients.     

Bioavailability of iron in hemodialysis patients treated with erythropoietin: evidence for the inhibitory role of aluminum

The dose of recombinant human erythropoietin (r-HuEPO) required to correct the anemia of end-stage renal disease (ESRD) varies among patients. The response to r-HuEPO is impaired if absolute or relative iron deficiency exists. Aluminum may cause a microcytic anemia in patients with ESRD, but the mechanism remains incompletely defined. Twenty-two patients in the Canadian Multicentre EPO trial were studied for 6 months. In this randomized double-blind placebo-controlled trial, free erythrocyte protoporphyrin (FEP) was used as an indicator of iron-deficient deficient erythropoiesis. The relationship of FEP to the estimates of iron availability (serum iron, transferrin saturation, ferritin) and iron utilization (corrected reticulocyte count, hemoglobin) was evaluated by multiple linear regression analysis. The effect of aluminum on FEP was evaluated by adjusting the statistical model for this variable. All patients were iron replete as assessed by serum ferritin. FEP was not related to serum aluminum before administration of r-HuEPO, but it was significantly correlated with aluminum in the treated group. In hemodialysis patients treated with r-HuEPO, the proportion of the variability explained by the parameters of iron utilization and iron availability was 0.27. The effect of aluminum increased this to 0.59. In hemodialysis patients not receiving r-HuEPO, the proportion of variability in FEP explained by the model increased from 0.16 to 0.28 by adjusting for aluminum. The data support the hypothesis that aluminum interferes with the bioavailability of stored iron for erythropoiesis and thus may result in a microcytic anemia in patients with ESRD or may blunt their response to r-HuEPO therapy.     

Perioperative erythropoietin administration in patients with gastrointestinal tract cancer: prospective randomized double-blind study

OBJECTIVE: To investigate the effect of recombinant human erythropoietin (r-HuEPO) administration on perioperative hemoglobin concentrations and on the number of blood transfusions in patients undergoing surgery for gastrointestinal tract malignancies. SUMMARY BACKGROUND DATA: Erythropoietin has been shown to improve the yield of autologously predonated blood and to reduce the subsequent requirements for homologous blood transfusions in cancer patients. METHODS: In this double-blind placebo-controlled study, 31 cancer patients received subcutaneous r-HuEPO in a dose of 300 IU/kg body weight plus 100 mg iron intravenously (study group) and 32 patients received placebo medication and iron (control group). All patients received the medications daily for at least 7 days before and 7 days after the operation. RESULTS: Patients who received erythropoietin received significantly fewer transfusions intraoperatively and postoperatively. Postoperatively, the study group had significantly higher hematocrit, hemoglobin, and reticulocyte count values compared to the control group. The use of erythropoietin was also associated with a reduced number of postoperative complications and improved 1-year survival. CONCLUSIONS: Patients with gastrointestinal tract cancer and mild anemia benefit from perioperative erythropoietin administration in terms of stimulated erythropoiesis, reduction in the number of blood transfusions, and a favorable outcome.     

Transferrin saturation versus reticulocyte hemoglobin content for iron deficiency in Japanese hemodialysis patients

BACKGROUND: Iron deficiency is a frequent cause of recombinant human erythropoietin (rhEPO)-resistant anemia in hemodialysis patients. Both reticulocyte hemoglobin content (CHr) and transferrin saturation (TSAT) have been proposed as markers of iron deficiency, but it is unclear which parameter is superior. METHODS: To compare the efficacy of CHr and TSAT as an indicator for treatment of iron deficiency, we conducted a single-center, open-label, prospective, randomized, controlled trial at the Kidney Center in Shinraku-en Hospital of 197 Japanese patients on chronic hemodialysis. After 4 weeks of run-in period during which iron supplementation was suspended, 100 patients who were randomized to the CHr group received 240 mg iron colloid intravenously over 2 weeks when CHr less than 32.5 pg, and 97 patients who were randomized to the TSAT group received the same doses of iron colloid when TSAT less than 20%. We measured the rhEPO dose needed to maintain prestudy hematocrit levels, hematocrit, CHr, TSAT, serum ferritin, percentage of hypochromic red blood cells, and total iron administered. RESULTS: Sixteen weeks later, 94 patients in the CHr group and 89 patients in the TSAT group finished the study. The doses of rhEPO required decreased by 35.8% (4081 to 2629 U/week, P < 0.005) in the TSAT group, but not significantly in the CHr group (4121 to 3606 U/week). Although CHr increased promptly after the iron administration in both groups, TSAT increased only in the TSAT group. CONCLUSIONS: Although CHr reflects the iron status more sensitively, TSAT is a better clinical marker for iron supplementation therapy.     

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.     

Factors determining the percentage of hypochromic red blood cells in hemodialysis patients.

Factors determining the percentage of hypochromic red blood cells determines iron status in hemodialysis patients. BACKGROUND: Determination of the percentage of hypochromic red blood cells (RBC; %HYPO) has been advocated as a sensitive index of functional iron deficiency during erythropoietin (EPO) therapy in hemodialyzed patients. METHODS: The significance of %HYPO in chronic renal failure was evaluated in 64 chronically hemodialyzed patients. The linear correlation was determined between %HYPO and 13 variables, including age, sex, weight, C-reactive protein (CRP), ferritin, transferrin (Tf), Tf saturation, soluble Tf receptor (sTfR), serum iron (SI), urea, parathormone, dialysis dose (Kt/V), dose of EPO administered (EPO), and absolute reticulocyte count. Multiple regression analyses were then performed to select the parameters that jointly provide the best prediction of %HYPO. RESULTS: Univariate analysis showed significant correlations between %HYPO and iron parameters (sTfR, Tf saturation, SI, and ferritin, in decreasing order), EPO, reticulocyte count, and CRP. Multivariate analysis yielded an equation showing that the variation of %HYPO is essentially associated with the combined changes in sTfR, CRP, and EPO dosage. CONCLUSIONS: %HYPO is a meaningful and inexpensive parameter that reflects the integrated effects of iron stores, inflammation, and erythropoietic stimulation on iron availability in hemodialyzed patients. Among iron exchange parameters, sTfR is the best predictor of %HYPO, followed by Tf saturation, SI, and ferritin.     

Sirolimus interferes with iron homeostasis in renal transplant recipients

BACKGROUND: Sirolimus is an immunosuppressive drug whose use is frequently associated with anemia. A pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we investigated whether sirolimus may influence iron homeostasis and serum levels of hepcidin, a key mediator of inflammation-related anemia. METHODS: To this purpose, 42 consecutive transplanted patients with biopsy-proven chronic allograft nephropathy were randomized (2:1 ratio) to receive either a 40% cyclosporine reduction (group A, 14 patients) or immediate cyclosporine withdrawal and sirolimus introduction (group B, 28 patients). Hemoglobin levels and iron status were evaluated 6 months before and after randomization. RESULTS: The two groups had similar hemoglobin levels and iron status at baseline. We did not observe any significant change in hemoglobin and iron status in group A patients after randomization. On the contrary, we observed a significant reduction of hemoglobin without any change of red blood cell count after sirolimus introduction, with a significant reduction of mean corpuscular volume and mean corpuscular hemoglobin. Serum iron and transferrin saturation (TSAT) levels were markedly reduced after the switch, while ferritin serum concentrations remained stable. Although sirolimus-induced anemia was recently suggested to resemble inflammation-related anemia, hepcidin serum levels were similar in the two groups after randomization. None of group A and eight of group B patients presented a TSAT <20 and were given iron supplementation after randomization, in all of them oral iron therapy did not influence either hemoglobin or serum iron levels. CONCLUSION: We demonstrated that sirolimus-induced anemia is independent of the drug antiproliferative effect and does not present the features of inflammation-related anemia. This event may be due to the direct influence of sirolimus on iron homeostasis.     

Metabolism, oxygen transport, and erythropoietin synthesis in the anemia of thermal injury

The relationship between metabolism, oxygen transport, and anemia was assessed in burn patients. A significant negative correlation was found between erythrocyte 2,3 DPG, the major modulator of oxygen transport, and erythropoietin synthesis. Simultaneous bioassay and radioimmunoassay for erythropoietin revealed elevated values in the anemic burn patients. Elevated 2,3 DPG values during convalescence from thermal injury may remove the "anemic hypoxia" stimulus to erythropoieitn production, resulting in persistence of the anemia.     

Efficacy of quadruple treatment on different types of pre-operative anaemia: secondary analysis of a randomised controlled trial

In patients with pre-operative anaemia undergoing cardiac surgery, combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12 and oral folic acid reduces allogeneic blood product transfusions. It is unclear if certain types of anaemia particularly benefit from this treatment. We performed a post-hoc analysis of anaemic patients from a randomised trial on the ‘Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery’. We used linear regression analyses to examine the efficacy of a combination anaemia treatment compared with placebo on the following deficiencies, each representing a part of the combination treatment: ferritin and transferrin saturation; endogenous erythropoietin; holotranscobalamine; and folic acid in erythrocytes. Efficacy was defined as change in reticulocyte count from baseline to the first, third and fifth postoperative days and represented erythropoietic activity in the immediate peri-operative recovery phase. In all 253 anaemic patients, iron deficiency was the most common cause of anaemia. Treatment significantly increased reticulocyte count in all regression analyses on postoperative days 1, 3 and 5 (all p < 0.001). Baseline ferritin and endogenous erythropoietin were negatively associated with change in reticulocyte count on postoperative day 5, with an unstandardised regression coefficient B of −0.08 (95%CI −0.14 to −0.02) and −0.14 (95%CI −0.23 to −0.06), respectively. Quadruple anaemia treatment was effective regardless of the cause of anaemia and its effect manifested early in the peri-operative recovery phase. The more pronounced a deficiency was, the stronger the subsequent boost to erythropoiesis may have been.     

Hypochromic red cells and reticulocyte haemglobin content as markers of iron-deficient erythropoiesis in patients undergoing chronic haemodialysis.

BACKGROUND: In patients on chronic haemodialysis, because of a non-specific increase in serum ferritin, iron deficiency may be overlooked leading to failure of erythropoietin treatment. A reticulocyte haemglobin content < 26 pg and a percentage of hypochromic red cells > 2.5 have been proposed as markers of iron-deficient erythropoiesis in such subjects, but it is unclear which parameter is superior. METHODS: We measured haematocrit, reticulocyte haemglobin content, ferritin and the percentage of hypochromic red cells over 10-150 days in 36 chronic haemodialysis patients in a university hospital. Transferrin saturation was also measured in a subset of 25 patients; iron deficiency was defined as a transferrin saturation < 15%. RESULTS: The diagnostic sensitivity and specificity of a reticulocyte haemoglobin content < 26 pg in detecting iron deficiency were 100% and 73% respectively, compared with 91% and 54% for a percentage of hypochromic red cells > 2.5. Paradoxical reticulocyte haemglobin concentrations occurred on follow-up in five patients receiving 4000 U erythropoietin per haemodialysis (HD). In three patients, reticulocyte haemglobin content exceeded 26 pg despite a persistent lack of iron. In a fourth, iron gluconate (62.5 mg i.v./HD) increased transferrin saturation to 27% and reduced the percentage of hypochromic red cells from 12 to 4, while reticulocyte haemglobin remained > 30 pg. In the final patient, iron gluconate increased transferrin saturation from 8 to 30% and reduced the percentage of hypochromic red cells from 40 to below 5, but reticulocyte haemglobin content remained < or = 26 pg throughout. CONCLUSIONS: The reticulocyte haemglobin content is superior to the percentage of hypochromic red cells in detecting iron deficiency in haemodialysis patients.