Recombinant Human Erythropoietin Therapy Research Articles

Exploring dosing frequency and administration routes in the treatment of anaemia in CKD patients

Erythropoiesis-stimulating agents have dramatically changed the management of renal anaemia since their introduction almost 20 years ago. However, optimal dosing route and frequency are still a matter of debate. Intravenous application of recombinant human erythropoietin should be limited to haemodialysis patients and must be given three times weekly, as any reduction to this dosing frequency leads to a major increase in dose requirements. Administering recombinant human erythropoietin-beta once weekly via the subcutaneous route is effective. If conversion from the subcutaneous to the intravenous route is required, dose requirements for recombinant human erythropoietin therapy remain a subject of discussion.

Long‐term Erythropoietin Therapy Improves Response in Myelodysplastic Syndrome

We report on a 53-year-old Japanese female on hemodialysis with myelodysplastic syndrome whose condition improved with recombinant human erythropoietin (epoetin) therapy. In 1992, based on a diagnosis of folic acid deficiency anemia, folate derivatives were administered. However, the anemia did not improve, and red blood cells had to be transfused subsequently. The transfusion volume was gradually increased afterward, as renal failure progressed, probably due to nephropathy by phenacetin. In 1998, when hemodialysis started, epoetin therapy was started with a dose of 3000 units three times per week. In July 2001, myelodysplastic syndrome (MDS) of a refractory anemia type was diagnosed through bone marrow aspiration. Myelodysplastic syndrome might cause an epoetin-resistant renal anemia. Afterwards the transfusion volume was gradually reduced, and transfusions were not performed after March 2002. Improvements of histological findings of MDS as well as anemia were confirmed by bone marrow aspiration in July 2003. This is an unusual case of a patient with a previously existing MDS, who subsequently develops end stage renal disease, and has an amelioration of her underlying MDS with the administration of epoetin over a long-term period, while being treated with chronic hemodialysis, even when not effective for a short-term.

Non-Occlusive Mesenteric Ischemia in Chronically Dialyzed Patients: A Disease with Multiple Risk Factors

Background: Non-occlusive mesenteric ischemia (NOMI) can be a fatal complication in dialysis patients. Intradialytic hypotension is usually the precipitating factor. The occurrence of 16 cases in 5 years (1998–2002), compared with only 4 in previous years, led us to investigate other risk factors contributing to NOMI. A control group of stable hemodialysis patients was used for comparison. Results: 20 patients were studied: 17 diagnosed surgically, and 3 clinically. The mean age was 70.8 ± 1.8 years, and the male:female ratio 7:13. Nineteen patients were on hemodialysis. Clinically overt atherosclerosis was present in 17 patients. Preceding dialysis-associated hypotension was identified in all patients studied and access thrombosis in 6 patients. In all patients, abdominal pain was the presenting symptom. Initial abdominal examination was unimpressive in 16 patients. The hemoconcentration, leukocytosis and metabolic acidosis were the most prominent laboratory findings. 5/11 abdominal sonograms showed intestinal pathology. 2/3 angiographies were diagnostic. Three patients responded to early fluid challenge and did not require surgery. Pathology was related to the area of the superior mesenteric artery in all 15 patients operated. Twelve (60%) patients died from the event. The 1-year mortality rate was 17/20 patients (85%). Possible contributing factors, other than dialysis-associated hypotension, included: high-dose recombinant human erythropoietin (rhEPO) therapy (179 ± 35 vs. 116 ± 10 U/kg/week in the control group, p < 0.05); metastatic calcifications (abdominal aorta 14/14, aortic valve 11/18; medial calcification of mesenteric arteries in 2/11 pathology specimens); digoxin, and hypoalbuminemia. Conclusions: The increased incidence of NOMI in dialysis patients may be related to overly aggressive rhEPO therapy and the unsuspected presence of mesenteric arterial medial calcifications. Identification of patients at risk, prevention of intradialytic hypotension and a controlled increase in dry weight may help to reduce the incidence of NOMI in chronically dialyzed patients.

Discrepancy between the Percentage of Hypochromic Erythrocytes and the Reticulocyte Hemoglobin Content in Hemodialysis Patients with Recombinant Human Erythropoietin Therapy

The percentage of hypochromic erythrocytes (%HYPO) and the reticulocyte hemoglobin content (CHr) have been used for the diagnosis of iron deficiency (ID). However, we found a discrepancy between %HYPO and CHr values in some hemodialysis patients. Hemodialysis patients receiving recombinant human erythropoietin (rHuEPO) with ID were defined as patients with a %HYPO value exceeding 5%. Five ID patients with a high CHr (group A) and 3 ID patients with a low CHr (group B) received 120 mg/week iron intravenously for 8 to 12 weeks. Changes in %HYPO, CHr, percentage of macrocytic erythrocytes (%MACRO), absolute reticulocyte count, immature reticulocyte fraction, and soluble transferrin receptor level were investigated over a 20-week period. CHrs were measured with 2 hematology analyzers: the Bayer HealthCare Technicon H*3 and the ADVIA 120. Patients in group A showed a significantly greater mean %MACRO (P < .01) and a lower mean red blood cell number (P < .05) than patients in group B. Even the mean CHr at baseline in group A was significantly higher than the mean CHr in the healthy subjects (P < .01), and hemoglobin levels increased in association with the reduction in rHuEPO dose following iron administration (P < .01). We found a group with high CHr, %HYPO, and %MACRO values among hemodialysis patients. Iron administration enables the rHuEPO dose to be reduced.

Levocarnitine and Dialysis: A Review

Among the various metabolic abnormalities documented in dialysis patients are abnormalities related to the metabolism of fatty acids. Aberrant fatty-acid metabolism has been associated with the promotion of free-radical production, insulin resistance, and cellular apoptosis. These processes have been identified as important contributors to the morbidity experienced by dialysis patients. There is evidence that levocarnitine supplementation can modify the deleterious effects of defective fatty-acid metabolism. Patients receiving hemodialysis and, to a lesser degree, peritoneal dialysis have been shown to be carnitine deficient, as manifested by reduced levels of plasma free carnitine and an increase in the acyl:free carnitine ratio. Cardiac and skeletal muscles are particularly dependent on fatty-acid metabolism for the generation of energy. A number of clinical abnormalities have been correlated with a low plasma carnitine status in dialysis patients. Clinical trials have examined the efficacy of levocarnitine therapy in a number of conditions common in dialysis patients, including skeletal-muscle weakness and fatigue, cardiomyopathy, dialysis-related hypotension, hyperlipidemia, and anemia poorly responsive to recombinant human erythropoietin therapy (rHuEPO). This review examines the evidence for carnitine deficiency in patients requiring dialysis, and documents the results of relevant clinical trials of levocarnitine therapy in this population. Consensus recommendations by expert panels are summarized and contrasted with present guidelines for access to levocarnitine therapy by dialysis patients.

Erythropoietin Increases Asymmetric Dimethylarginine in Endothelial Cells

Recombinant human erythropoietin therapy frequently causes hypertension in humans and animals with chronic renal failure. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase, and its accumulation has been associated with reducing NO bioavailability and increasing superoxide generation. Whether epoetin beta (EPO) or darbepoetin alpha (NESP) can modify the levels of ADMA in endothelial cells was investigated. Endothelial cells from the third passage were incubated for 24 h in the presence of various concentrations of EPO or NESP (0, 0.1, 1, 10, 50, 100, and 200 U/ml). The levels of ADMA, allantoin, nitrate, and nitrite in conditioned media and the activity of dimethylarginine dimethylaminohydrolase (DDAH), the content of thiols and reactive oxygen species in endothelial cells, were determined. When endothelial cells were exposed to EPO or NESP, ADMA concentration in the cell culture medium increased significantly in a dose-dependent manner versus control. This effect was associated with a reduced activity of DDAH, the enzyme that degrades ADMA. Furthermore, EPO- or NESP-induced accumulation of ADMA was accompanied by a significant reduction of NO synthesis and an increase in oxidative stress. Both allantoin, a marker of oxygen free radical generation, and reactive oxygen species increased significantly after EPO or NESP treatment compared with control. The antioxidant pyrrolidine dithiocarbamate preserved DDAH activity and reduced ADMA accumulation in the same way as the co-incubation with anti-EPO neutralizing antibody. EPO and NESP posttranslationally impair DDAH activity via increased oxidative stress, causing ADMA as an important cardiovascular risk factor to accumulate and inhibit NO synthesis.

Recombinant human erythropoietin therapy in low‐birthweight preterm infants: A prospective controlled study

This study aimed to detect the effectiveness of recombinant human erythropoietin therapy in preventing premature anemia in low-birthweight preterm infants. A total of 292 premature infants who were born earlier than 33 gestational weeks and smaller than 1500 g birthweight were enrolled into the study. In addition to their conventional supportive therapy (medications), recombinant human erythropoietin 200 U/kg twice a week, subcutaneously, was given to randomly selected 142 premature infants for 6 weeks. The blood count variables and need for transfusions were compared with the remaining 150 premature infants during 6 months follow up. Serum erythropoietin levels were 11.3 +/- 6.1 mU/mL and 38.3 +/- 19.1 mU/mL in the erythropoietin group before and at the fourth week of the study, respectively (P < 0.001). Reticulocyte counts of the group treated with erythropoietin were 146 x 10(6) +/- 28 x 10(6)/mL and 122 x 10(6) +/- 27 x 10(6)/mL at the fourth and seventh week of the study, respectively, and these values were significantly higher when compared with the control group (P < 0.001 and P < 0.001). At the same period, hematocrit values were also found to be higher in the treatment group than the control group (P < 0.001). Serum ferritin levels were lower in the treatment group compared with the control group at the fourth week of the study. No side-effects related to erythropoietin usage were encountered. The need for packed cell transfusions were 47% in the group treated with erythropoietin and 62.6% in the control group. A statistically significant difference was found for transfusion needs between the control and treatment groups (P < 0.001). Recombinant erythropoietin is effective therapy for maintaining stable hematocrit levels in low-birthweight preterm infants and prevents the need for blood transfusions.

Intractable anemia among hemodialysis patients: A sign of suboptimal management or a marker of disease?

Most incident hemodialysis (HD) patients who initiate dialysis therapy with anemia usually can achieve a hemoglobin (Hb) level of 11 g/dL or greater (> or =110 g/L) within a few months of the initiation of recombinant human erythropoietin (EPO) therapy. However, patients unable to achieve this level may be at greater risk for adverse outcomes. Whether intractable anemia is a modifiable problem or a marker for other conditions is unclear. This question was addressed in a cohort of 130,544 incident HD patients from 1996 to 2000 who were administered EPO regularly. Medicare claims data were used to determine demographic characteristics, comorbidities, hospitalizations, and related events. Patients who did not achieve an Hb level of 11 g/dL or greater (> or =110 g/L; n = 19,096; 14.6%) during months 4 to 9 after dialysis therapy initiation were compared with those who did. Patients unable to achieve an Hb level of 11 g/dL (110 g/L) were younger and more often of nonwhite race. In addition, these patients had more comorbid conditions; experienced more hospitalizations with longer stays, more infectious hospitalizations, and more catheter insertions; and were administered more blood transfusions. EPO was administered in higher and increasing doses during the years of study among patients with intractable anemia compared with those with an Hb level of 11 g/dL or greater (> or =110 g/L), likely denoting increasing attempts to correct anemia over the years. It is apparent that incident HD patients unable to achieve an Hb level of 11 g/dL or greater (> or =110 g/L) have a greater disease burden. The independent association of intractable anemia with such future outcomes as cardiovascular events and hospitalizations remains to be determined.

Mechanisms and treatment of anemia in chronic heart failure.

Anemia is highly prevalent in patients with chronic heart failure (HF) and is associated with poor clinical outcomes. Multiple mechanisms contribute to anemia in chronic HF, and subnormal compensatory rise in endogenous erythropoietin levels in response to anemia is one contributory factor. Randomized trials with recombinant human erythropoietin therapy in anemic patients with chronic kidney disease and concomitant heart disease have demonstrated a reduction in left ventricular hypertrophy but variable effects on clinical outcome. Preliminary clinical trials in anemic patients with chronic HF demonstrate that erythropoietin therapy is well tolerated and associated with short-term clinical improvement. The optimum target hemoglobin, erythropoietic agent, and dosing regimen, and the role of iron supplementation in patients with chronic HF, are not known. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in chronic HF patients.

Reticulocyte hemoglobin content in hemodialysis patients with acute infection.

Reticulocyte hemoglobin content (CHr) has recently become available as a direct marker of the iron status in hemodialysis patients undergoing recombinant human erythropoietin (rHuEPO) therapy. This study evaluated the stability of CHr in hemodialysis patients with acute infectious disease. We retrospectively selected 22 hemodialysis patients who had acute respiratory tract infection and who showed transient elevation of C-reactive protein (CRP), and we investigated changes in parameters for erythropoiesis, iron status, and inflammation, i.e., hematocrit (Ht), transferrin saturation (TSAT), CHr, serum ferritin, and CRP, in the preinfection, infection, and postinfection phases. Throughout the observation period, doses of rHuEPO and iron supplements had not been changed. We divided the patients into two groups, those who showed a decrease in Ht in the infection phase (group 1; n = 12) and those who did not show a change in Ht in this phase (group 2; n = 10). We defined the differences between the parameters in the preinfection phase and the infection phase as Delta, and performed correlation analysis between them. CRP in group 1 was significantly higher than that in group 2 in the infection phase. In group 1, TSAT significantly decreased, from 32.9 +/- 8.8% (preinfection phase) to 16.9 +/- 5.0% (infection phase), and CHr also significantly decreased, from 33.1 +/- 1.5 pg to 30.4 +/- 2.0 pg. In group 2, however, although TSAT significantly decreased, from 34.8 +/- 4.6% to 27.0 +/- 9.3%, CHr showed no significant change (from 33.4 +/- 0.9 pg to 33.0 +/- 1.4 pg). There was a significantly high correlation between DeltaHt and DeltaCHr, but there was a low correlation between DeltaHt and DeltaTSAT ( r = 0.505; P = 0.0153 versus r = 0.175; P = 0.4420). Furthermore, the correlation between DeltaCRP and DeltaCHr was quite high ( r = -0.722; P = 0.0001). TSAT overreacts to inflammation, failing to reveal the correct status of available iron for erythropoiesis in acute inflammatory disease, but the use of CHr is expected to avoid these disadvantages, providing a reliable direct marker of iron status in the acute infection phase.

Recombinant human erythropoietin in anemic heart failure patients

Background: Heart failure (HF) is associated with anemia due to complex mechanisms. A few studies allude to improvements in symptoms and objective measures in HF patients with recombinant human erythropoietin (rHuEpo) and iron therapy. We analyzed the effect of this therapy in patients treated at our center from January 2000 to October 2003 during which time a clinical protocol offered rHuEpo treatment. Methods: We reviewed the charts of 467 HF patients treated at our center during that period. Records of rHuEpo administration were obtained from the hospital pharmacy database. The rHuEpo was administered to patients with hemoglobin (Hb) 11 g/dL accompanied with oral iron supplementation. Dose was adjusted to the severity of anemia. Follow-up was on average 438 336 days after treatment had begun. Results: Eighty-one (52 men and 29 women, average age 64 13 years) of 179 anemic HF patients (Hb 11 g/dL) were treated with rHuEpo. Twenty-six (38%) of these patients were classified as NYHA class IV, 34 (49%) as class III and 9 (13%) as class II. The average Hb level before rHuEpo therapy was 9.9 1.1 g/dL, during therapy 12.3 1.5 g/dL, (P 0.0001), and 1 month after therapy 11.7 1.7 g/dL (P 0.0001). BUN level before therapy was 51 31 mg/dL. The BUN level after therapy decreased to 38 23 mg/dL (P 0.041). We compared 60 patients NYHA III or IV treated with rHuEpo to 60 non–treated NYHA matched controls. Groups were comparable (P 0.1) regarding age, body weight, gender, and BNP. QTc interval was longer in the rHuEpo group 483 63 ms vs. 461 50 ms (P 0.003). Treated patients had worse renal function at baseline: BUN 54 33 mg/dL, vs. 35 24 mg/dL (P 0.001); creatinine 2.1 1.7 mg/dL vs. 1.6 0.8 mg/dL (P 0.04). Hospital admissions in treated patients decreased during 6 months before and after therapy from 2.0 1.7 to 1.0 1.4, P 0.0004. This number of hospital admissions after therapy was lower than the average number during 6 months in controls 1.7 1.8, P 0.019. Although signs of worse pretreatment health in rHuEpo patients were present, no difference in mortality rate (12/60 [20%] vs. 19/60 [32%], P 0.144), or adverse clinical events like deep vein thrombosis (2% vs. 2%), cerebral vascular accidents (15% vs. 13%), or transient ischemic attacks (2% vs. 8%) was noted between rHuEpo group and controls, respectively. Conclusion: Anemic HF patients benefit from erythropoietin therapy in terms of correction of anemia, improved renal function and decreased need for hospitalization without an increase in adverse effects. 363

A controlled, randomized, open-label study to evaluate the effect of every-2-week darbepoetin alfa for anemia of cancer

8084 Background: Patients (pts) with cancer who are not receiving chemotherapy (ctx) or radiotherapy (rtx) often develop anemia. A previous randomized, controlled trial evaluating the effect of recombinant human erythropoietin therapy vs placebo on transfusion (tfn) incidence in this pt population failed to show a significant reduction in tfn requirements in treated pts, relative to control (Abels, 1991). This multicenter, randomized, controlled, 25-week (wk) study is closed to enrollment (n = 298) and was designed to assess the effect of darbepoetin alfa (DA; Aranesp®) in pts with anemia of cancer (AOC) with respect to hospitalization, incidence of tfn, and pt-reported outcomes. Methods: Eligible pts (anemia [hemoglobin (Hb) ≤ 11 g/dL]) due to cancer or prior ctx and/or rtx; had no ctx or rtx within 4 wks before screening or during the study) were randomized 4:1 to DA 3.0 mcg/kg every 2 weeks [Q2W] for 21 wks (DA arm) or 12 wks of observation followed by 9 wks of DA 3.0 mcg/kg Q2W (control arm). Data were analyzed using an intent-to-treat approach. Results are provided for all pts and stratified by baseline (BL) Hb category. Results: Data through the comparative phase (first 12 wks) were analyzed for the first 170 pts (135 DA, 35 control) enrolled. BL Hb was 10.2 (SD: 0.9) in the DA arm and 10.3 (0.9) in the control arm. Efficacy results (with 95% CL) are shown below. The safety profile was as expected for this population. Conclusions: These results show that AOC pts treated with darbepoetin alfa Q2W (vs no treatment) had marked improvements in Hb corresponding to clinically meaningful improvements in fatigue and a substantial reduction in tfn requirements. Importantly, the stratified analysis suggests that pts with AOC experience important clinical benefits, regardless of BL Hb category; however, earlier intervention (Hb >10 to <11g/dL) may optimize anemia management for this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen Amgen

A controlled, randomized, open-label study to evaluate the effect of every-2-week darbepoetin alfa for anemia of cancer

8084 Background: Patients (pts) with cancer who are not receiving chemotherapy (ctx) or radiotherapy (rtx) often develop anemia. A previous randomized, controlled trial evaluating the effect of recombinant human erythropoietin therapy vs placebo on transfusion (tfn) incidence in this pt population failed to show a significant reduction in tfn requirements in treated pts, relative to control (Abels, 1991). This multicenter, randomized, controlled, 25-week (wk) study is closed to enrollment (n = 298) and was designed to assess the effect of darbepoetin alfa (DA; Aranesp®) in pts with anemia of cancer (AOC) with respect to hospitalization, incidence of tfn, and pt-reported outcomes. Methods: Eligible pts (anemia [hemoglobin (Hb) ≤ 11 g/dL]) due to cancer or prior ctx and/or rtx; had no ctx or rtx within 4 wks before screening or during the study) were randomized 4:1 to DA 3.0 mcg/kg every 2 weeks [Q2W] for 21 wks (DA arm) or 12 wks of observation followed by 9 wks of DA 3.0 mcg/kg Q2W (control arm). Data were analyzed using an intent-to-treat approach. Results are provided for all pts and stratified by baseline (BL) Hb category. Results: Data through the comparative phase (first 12 wks) were analyzed for the first 170 pts (135 DA, 35 control) enrolled. BL Hb was 10.2 (SD: 0.9) in the DA arm and 10.3 (0.9) in the control arm. Efficacy results (with 95% CL) are shown below. The safety profile was as expected for this population. Conclusions: These results show that AOC pts treated with darbepoetin alfa Q2W (vs no treatment) had marked improvements in Hb corresponding to clinically meaningful improvements in fatigue and a substantial reduction in tfn requirements. Importantly, the stratified analysis suggests that pts with AOC experience important clinical benefits, regardless of BL Hb category; however, earlier intervention (Hb >10 to <11g/dL) may optimize anemia management for this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen Amgen

Novel uses for recombinant erythropoietin therapy in unlicensed indications.

Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.

Prospective trials on anemia of chronic disease: The Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT): Management of comorbidities in kidney disease in the 21st century: Anemia and bone disease

Chronic kidney disease (CKD) is emerging as a major public health problem in the United States. Between 1973 and 1999 there was a more than 30-fold increase in the number of patients enrolled in the Medicare funded end-stage renal disease (ESRD) program, from approximately 10,000 to 340,000 [1]. The annual incidence of ESRD has nearly doubled from 48,350 patients (190 per million) in 1991 to 89,252 (317 per million) in 1999. Estimates from the Third National Health and Nutrition Examination Survey (NHANES III), using the glomerular filtration rate (GFR) equation from the Modification of Diet in Renal Disease (MDRD) study [2, 3], showed that the prevalence of CKD, defined as a GFR 60 mL/min /1.73 m2, was approximately 8.3 million individuals, or 4.7% [4]. The MDRD Study indicated that 85% of patients with impaired kidney function (GFR 55 mL/min/1.73m2) have progressive losses of kidney function at a rate of 4 mL/min per year [5]. The progressive nature of CKD, and epidemiologic factors that include population aging, increasing prevalence of type II diabetes and hypertension, improved survival of patients on dialysis, and the acceptance of higher risk patients into ESRD programs, explain the ongoing and projected increases in the numbers of patients with ESRD. The increasing incidence and prevalence of ESRD and CKD is a global trend not just confined to the United States [6]. Although incidence rates for the United States and Japan are nearly two-fold higher than those of other industrialized nations, the rates of growth appear to be quite similar, best described by an exponential growth curve at the rate of 7.36% per year [7]. The impact of these numbers must be interpreted from

Inhibition of erythrocyte cation channels by erythropoietin.

Recombinant human erythropoietin therapy is used to counteract anemia that is the result of renal insufficiency. It stimulates the formation of peripheral blood erythrocytes by inhibiting apoptosis of erythrocyte precursor cells. Mature erythrocytes have similarly been shown to undergo apoptosis. Hyperosmotic shock and Cl(-) removal activate a Ca(2+)-permeable, ethylisopropylamiloride-inhibitable cation channel. The subsequent increase of cytosolic Ca(2+) activates a scramblase that breaks down cell membrane phosphatidylserine asymmetry, leading to annexin binding. Studied was whether channel activity and erythrocyte cell death are regulated by erythropoietin. Scatchard plot analysis disclosed low-abundance, high-affinity binding of (125)I-erythropoietin to erythrocytes. Whole cell patch clamp experiments revealed significant inhibition of the ethylisopropylamiloride-sensitive current by 1 U/ml erythropoietin. Cl(-) removal triggered annexin binding, an effect abrogated by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). Osmotic shock (700 mOsm) stimulated annexin binding within 24 h in the majority of the erythrocytes, an effect blunted by erythropoietin (1 U/ml) but not by GM-CSF (10 ng/ml). In the nominal absence of Ca(2+), the effect of osmotic shock was blunted and the effect of erythropoietin abolished. In hemodialysis patients, intravenous administration of erythropoietin (50 IU/kg) within 4 h decreased the number of annexin binding circulating erythrocytes. Erythropoietin binds to erythrocytes and inhibits volume-sensitive erythrocyte cation channels and thus the breakdown of phosphatidylserine asymmetry after activation of this channel. The effect could prolong the erythrocyte lifespan and may contribute to the enhancement of the erythrocyte number during erythropoietin therapy in dialysis patients.

Iron deficiency and erythropoiesis: new diagnostic approaches.

Iron deficiency anemia is one of the most common diseases worldwide. In the majority of cases, the presence of hypochromic microcytic anemia and biochemical evidence for depletion of body iron stores makes the diagnosis relatively straightforward. However, in several clinical conditions, classic biochemical indices such as serum iron, transferrin saturation, and ferritin may not be informative or may not change rapidly enough to reflect transient iron-deficient states (functional iron deficiency), such as the ones that develop during recombinant human erythropoietin (r-HuEPO) therapy. The identification and treatment of iron deficiency in settings such as r-HuEPO therapy, anemia of chronic disease, and iron deficiency of early childhood may be improved by the use of red cell and reticulocyte cellular indices, which reflect in almost real time the development of iron deficiency and the response to iron therapy. In the anemia of chronic disease, measurements of plasma cytokines and iron metabolism regulators such as hepcidin (when available) may be helpful in the characterization of the pathophysiologic basis of this condition. The ratio of serum transferrin receptor (sTfR) to serum ferritin (R/F ratio) has been shown to have excellent performance in estimating body iron stores, but it cannot be used widely because of the lack of standardization for sTfR assays. The combination of hematologic markers such as reticulocyte hemoglobin content, which decreases with iron deficiency, and R/F ratio may allow for a more precise classification of anemias.

Tandem high‐dose therapy (HDT) for multiple myeloma: recombinant human erythropoietin therapy given between first and second HDT allows second peripheral blood stem cell transplantation without red blood cell transfusion

We evaluated the ability of recombinant human erythropoietin (rHuEpo) therapy, given before high-dose therapy (HDT), to allow autologous peripheral blood stem cell transplantation (PBSCT) without red blood cell (RBC) transfusions. Eleven multiple myeloma patients underwent tandem HDT and autologous PBSC, receiving 500 U/kg/week rHuEpo from d 30 after initial transplant. Haemoglobin levels were 9.5 +/- 1.1 g/dl and 12.5 +/- 0.9 g/dl at the first and second transplant respectively (P < 0.001). RBC transfusions were required for 10/11 patients for the first transplant versus 1/11 for the second (P < 0.001). To conclude, a short course of rHuEpo therapy before HDT facilitates the performance of an autologous transplant without RBC transfusions.

Clinical evaluation of heme iron polypeptide: sustaining a response to rHuEPO in hemodialysis patients

Background:Optimizing iron and recombinant human erythropoietin (rHuEPO) therapy is necessary to achieve target hemoglobin levels and minimize costs as the end-stage renal disease (ESRD) population expands. Oral iron products in patients with ESRD have been largely abandoned, and the safety of intravenous (IV) iron preparations has improved with the introduction of new-generation compounds that have little allergenicity. Recent work suggests oral heme iron may be an effective supplement for hemodialysis (HD) patients because it is absorbed by patients with high ferritin levels, has fewer side effects, and its absorption is stimulated by erythropoietin administration. Methods:We performed an open, 6-month, prospective evaluation of heme iron in HD patients who had been on maintenance IV iron therapy. IV iron was discontinued and replaced with oral heme iron. Serum iron level, hematocrit (Hct), and erythropoietin and IV iron dose were monitored. Results:During 6 months, 4 of 37 patients (11%) dropped out because of insufficient iron supplementation or intolerance and 5 patients (14%) were dropped because of unrelated complications or protocol violation. A slight reduction in average transferrin saturation (TSAT) was seen early, but reversed, and no significant changes were seen in TSAT or Hct. A significant reduction in average serum ferritin level was seen at months 4 through 6 (P < 0.01). Conclusion:During the 6-month study period, heme iron polypeptide successfully replaced IV iron therapy in a majority of HD patients and maintained target Hcts with no concomitant use of IV iron. This treatment was associated with a significant increase in rHuEPO efficiency (P = 0.04).

The advantages of intravenous renal anaemia treatment in an undernourished patient with chronic kidney disease

SUMMARYThe subcutaneous (SC) treatment of renal anaemia in undernourished patients has potential limitations. In this case report we demonstrate the value of intravenous (IV) darbepoetin alfa in such a patient who experienced difficulty tolerating SC recombinant human erythropoietin (rHuEPO) therapy due to severe malnutrition. Intravenous treatment of renal anaemia in a malnourished patient is preferred because the absence of SC fat makes SC administration difficult. In such patients, darbepoetin alfa is the treatment of choice as it is administered less frequently than other erythropoietic therapies and yis more effective at maintaining target haemoglobin (Hb) concentrations. In contrast to rHuEPO, darbepoetin alfa also has the additional advantage of bioequivalent IV and SC dose requirements.