Recombinant Human Erythropoietin Therapy Research Articles

New insights into the thrombopoietic status of patients on dialysis through the evaluation of megakaryocytopoiesis in bone marrow and of endogenous thrombopoietin levels

AbstractThe thrombopoietic status of patients with uremia remains unclear. This issue was addressed with particular reference to marrow megakaryocytopoiesis and endogenous thrombopoietin (TPO) levels. A study was conducted in 114 patients on hemodialysis, 43 patients on continuous ambulatory peritoneal dialysis, and 48 age-matched controls. Reticulated platelets, a marker of marrow megakaryocytopoiesis, were measured by flow cytometry. Serum TPO levels, platelet-associated IgG (PAIgG) levels, and hepatitis C virus (HCV) antibody titers were also measured by enzyme-linked immunosorbent assay. Circulating and reticulated platelet counts were significantly lower in the patients on dialysis than in the controls. Thrombocytopenia (less than 150 × 109/L) was most frequent in the HCV-positive hemodialysis patients, who had a higher incidences and higher PAIgG titers. The following results were obtained in the HCV-negative dialysis patients: (1) platelet counts chronologically decreased with years on hemodialysis; (2) platelet counts were associated with the reticulated platelet counts; (3) serum TPO levels were significantly elevated in the dialysis patients, responding to the decrease of reticulated platelets; (4) hematocrits had a positive correlation with serum TPO levels, and serum TPO levels were significantly higher in the patients on hemodialysis who did not require recombinant human erythropoietin therapy than in the other patients. In conclusion, thrombocytopenia is a frequent finding in patients on dialysis. The failure of megakaryocyte production could be the principal cause of the platelet reduction, and the peripheral destruction and sequestration of platelets may be concomitantly involved. Elevation of serum TPO may in part serve as an aid to erythropoiesis in dialysis patients.

Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients.

Partial correction of anaemia with recombinant human erythropoietin (rHuEpo) has been shown to markedly improve the general condition and quality of life of predialysis patients, but the effects of rHuEpo therapy on blood pressure and the rate of progression of chronic renal failure (CRF) are still disputed. In particular, no study evaluated the time duration until the start of maintenance dialysis in treated patients, compared to untreated predialysis patients. We retrospectively evaluated the rate of decline of creatinine clearance (Delta Ccr) and the duration of the predialysis period in 20 patients with advanced CRF treated with rHuEpo (Epo+ group), and in 43 patients with a similar degree of CRF but with less marked, asymptomatic anaemia, not requiring rHuEpo therapy (Epo- group). All patients were submitted to identical clinical and laboratory surveillance. All received similar oral supplementation with B(6), B(9), and B(12) vitamins and oral iron supplementation. Maintenance dose of subcutaneous epoetin was 54.3+/-16.5 U/kg/week (median dose 3300 U/week). Initial and final haemoglobin (Hb) levels were 8.8+/-0.7 and 11.3+/-0.9 g/dl in the Epo+ group, vs 10.9+/-1.2 and 9.5+/-0.9 g/dl in the Epo- group. In the Epo+ group, Delta Ccr declined from 0.36+/-0.16 during the preceding 24 months to 0.26+/-0.15 ml/min/ 1.73 m(2)/month after the start of rHuEpo therapy (P<0.05). No significant variation was observed in the Epo- group. Time duration until the start of dialysis was 16.2+/-11.9 in the Epo+ group, compared to 10.6+/-6.1 months in the Epo- group (P<0.01). Slowing of progression was observed in 10 Epo+ patients, whereas no significant variation in Delta Ccr occurred in the other 10. There was no difference in previous Delta Ccr rate, nor in Hb or blood pressure levels while on rHuEpo therapy between the two subgroups. Our study affords conclusive evidence that rHuEpo therapy did not result in accelerated progression of CRF in any treated predialysis patients, nor deleterious increase in blood pressure, but instead resulted in significant slowing of progression and substantial retardation of maintenance dialysis. Such encouraging results remain to be validated in a large prospective, randomized study.

Cessation of intensive treatment with recombinant human erythropoietin is followed by secondary anemia

AbstractLittle information is available on the evolution of erythropoiesis after interruption of recombinant human erythropoietin (rHuEpo) therapy. Iron-overloaded rats received 20 daily injections of rHuEpo. During treatment, reticulocytes, soluble transferrin receptor (sTfR), and hematocrit increased progressively. This was accompanied by a substantial expansion of spleen erythropoiesis but a decrease in the bone marrow. Five weeks after treatment, rats developed a significant degree of aregenerative anemia. Erythropoietic activity, as assessed by reticulocytes, sTfR, erythroid cellularity, iron incorporation into heme, and the number of erythroid colonies, was severely depressed 3 weeks after cessation of rHuEpo. This was followed by regeneration of erythroblasts and reticulocytes at weeks 6 to 7 post-Epo, but erythroid progenitors recovered only partially by that time. The anemia was definitely corrected 2 months after cessation of rHuEpo treatment. Serum Epo levels remained elevated for several weeks, but the sensitivity of marrow erythroid precursors to Epo was preserved. No rat antibodies to rHuEpo were detected, and serum from post-Epo animals did not exert any inhibitory activity on erythropoiesis. In conclusion, after cessation of intensive rHuEpo therapy, there was a strong inhibition of erythropoietic activity with secondary anemia followed by late recovery. This was not due to antibodies or other soluble inhibitory factors, a defect in endogenous Epo production, or a loss of sensitivity to Epo. This may rather represent intrinsic erythroid marrow exhaustion, mostly at the level of erythroid progenitors but also at later stages of erythropoiesis.

The effect of recombinant human erythropoietin on serum selenium levels in hemodialysis patients

Successful results in the treatment of anemia, one of the main complications of chronic renal failure, can be achieved by the use of recombinant human erythropoietin (RhEPO), which is available almost fifteen years in clinics. On the other hand, as both chronic renal failure and maintenance hemodialysis reduce the levels of trace elements, this study was designed to evaluate the interaction potential of RhEPO with serum concentrations of selenium (Se) during four months. Thirty one adult hemodialysis outpatients participated in the study. Ten of them, not on any drug therapy to interact with RhEPO, recruited as “Control Group”, and the remainder, on RhEPO therapy, as “RhEPO Group”. Blood was drawn from the Control Group at the beginning of the study, and from the RhEPO Group at every month for four months. Serum erythropoietin levels were measured by a radioimmunoassay method and Se status by a spectrofluorometric method. It was found that Se levels were not affected by RhEPO treatment during 3 months of therapy, while an increase was seen on the fourth month. The observation indicates that the increase in serum Se levels would be significant in longer than three-month RhEPO treatment.

Changes of endogenous erythropoietin level and iron status during a 30-month hemodialysis treatment of a group of patients.

In our earlier paper we found that among 50 hemodialysis patients (HD pts) 48% (24 pts) control anemia with hemoglobin (Hb) concentration >9.5 g/dl and hematocrit (Hct) >30% without recombinant human erythropoietin (rHuEpo) therapy. These HD pts had significantly higher mean endogenous erythropoietin (eEpo) level and lower iron reserves (IR) than HD pts who need rHuEpo therapy. The aim of this study was to judge whether the possibility to control anemia in pts not requiring rHuEpo therapy changes during a 30-month HD treatment. Serum eEpo and ferritin were measured every 6 months. After 30 months of HD treatment 18 pts remained in this group--5 pts died, 1 underwent transplantation. During the study period 4/18 pts permanently had a very low level of eEpo (under detection limit), 7/18 had the level of eEpo within normal range for healthy control, 7/18 pts had a high level of eEpo (up to 3 times higher than the mean for healthy control). Pts who had the highest level of eEpo had the lowest IR. After 30 months IR were significantly lower than at the beginning of observation (292 +/- 87 vs 143 +/- 127 mg). Important negative correlation between eEpo and IR was observed throughout the whole period of study: r = -0.4820, p < 0.02 at the start of the study, and r = -0.6126, p < 0.007 after 30 months of treatment. The study shows that the possibility to control anemia in pts not treated with rHuEpo did not change significantly during 30 months of HD treatment. Endogenous Epo level in HD pts not treated with rHuEpo varied between different pts: it was permanently low in some pts, permanently high in others and stayed normal in remaining pts.

Effect of Weekly or Successive Iron Supplementation on Erythropoietin Doses in Patients Receiving Hemodialysis

Aims: To conduct a 3-month prospective study to determine the optimal way for intravenous iron supplementation in hemodialysis (HD) patients with resistance to recombinant human erythropoietin (rHuEPO) therapy due to deficient iron storage. Methods: Thirty-five HD patients with iron deficiency were divided into three groups: (1) patients receiving an intravenous infusion of 40 mg of iron during the first ten HD sessions (n = 12); (2) patients receiving 40 mg of iron injected once a week for 10 weeks (n = 12), and (3) patients without any iron supplementation (n = 11). The rHuEPO dosage was adjusted to maintain hemoglobin levels >10.0 g/dl, and the degree of anemia was assessed 3 months later. Results: In group 1, the hemoglobin levels were significantly increased after 4 weeks and remained increased until the end of the study (p < 0.01). In group 2, the hemoglobin levels were gradually increased until the end of the study (p < 0.01). There was no difference in the final hemoglobin values between both groups. The rHuEPO dosage was significantly decreased from 131 ± 18 to 90 ± 17 U/kg/week in group 1 (p < 0.01), but could not be changed in group 2 during the observation period despite a similar elevation of the serum ferritin level. In group 3, the rHuEPO doses were rather increased at the end of the study (p < 0.05). Conclusion: Aggressive iron supplementation for the short term may be effective to restore rHuEPO hyporesponsiveness in HD patients with functional iron deficiency.

Adequacy of dialysis reduces the doses of recombinant erythropoietin independently from the use of biocompatible membranes in haemodialysis patients.

The effect of the adequacy of dialysis on the response to recombinant human erythropoietin (rHuEpo) therapy is still incompletely understood because of many confounding factors such as iron deficiency, biocompatibility of dialysis membranes, and dialysis modality that can interfere. We investigated the relationship between Kt/V and the weekly dose of rHuEpo in 68 stable haemodialysis (HD) patients (age 65+/-15 years) treated with bicarbonate HD and unsubstituted cellulose membranes for 6-343 months (median 67 months). Inclusion criteria were HD for at least 6 months, subcutaneous rHuEpo for at least 4 months, transferrin saturation (TSAT) > or = 20%, serum ferritin > or = 100 ng/ml, and haematocrit (Hct) level targeted to 35% for at least 3 months. Exclusion criteria included HBsAg and HIV positivity, need for blood transfusions or evidence of blood loss in the 3 months before the study, and acute or chronic infections. Hct and haemoglobin (Hb) levels were evaluated weekly for 4 weeks; TSAT, serum ferritin, Kt/V, PCRn, serum albumin (sAlb), and weekly dose of rHuEpo were evaluated at the end of observation. No change in dialysis or therapy prescription was made during the study. The results for the whole group of patients were: Hct 35 +/- 1.2%, Hb 12.1 +/- 0.6 g/dl, TSAT 29 +/- 10%, serum ferritin 204 +/- 98 ng/ml, sAlb 4.1 +/- 0.3 g/dl, Kt/V 1.33 +/-0.19, PCRn 1.11+/- 0.28 g/kg/day, weekly dose of rHuEpo 123 +/- 76 U/kg. Hct did not correlate with Kt/V, whereas rHuEpo dose and Kt/V were inversely correlated (r = -0.49; P < 0.0001). Multiple regression analysis with rHuEpo as dependent variable confirmed Kt/V as the only significant variable (P < 0.002). Division of the patients into two groups according to Kt/V (group A, Kt/V < or = 1.2; group B, Kt/V > or = 1.4), showed no differences in Hct levels between the two groups, while weekly rHuEpo dose was significantly lower in group B than in group A (group B, 86 +/- 33 U/kg; group A, 183 +/- 95 U/kg, P < 0.0001). In iron-replete HD patients treated with rHuEpo in the maintenance phase, Kt/V exerts a significant sparing effect on rHuEpo requirement independent of the use of biocompatible synthetic membranes. By optimizing rHuEpo responsiveness, an adequate dialysis treatment can contribute to the reduction of the costs of rHuEpo therapy.

Ratio of baseline erythropoietin (EPO) level and corrected reticulocyte count as an indicator for a favourable response to recombinant human erythropoietin (rhEPO) therapy in anaemic cancer patients.

Recently, recombinant human erythropoietin (rhEPO) was introduced for the management of anemia in malignancy. To identify an indicator for a favourable response to rhEPO, 28 anaemic cancer patients undergoing chemotherapy and treated with rhEPO were evaluated. Patients were classified into responder (16 of 28, 57%) and nonresponder (12 of 28, 43%) groups according to their responses to rhEPO therapy (response being defined as an increase in Hb level of > 2 g/dl from baseline without blood transfusion). Treatment with rhEPO showed significant improvements in the red blood cell (RBC) count, haemoglobin (Hb), packed cell volume (PCV), and reticulocyte count (ret. count) after 4 weeks. Upon analysing the baseline value of the EPO level and the corrected ret.count in these two groups, we found that the ratio of the EPO level and the corrected ret.count (EPO/ret.count) demonstrated a statistical significance (P = 0.03) in the prediction of response to rhEPO therapy. This ratio showed a sensitivity of 87.5%, specificity of 66.7%, and overall accuracy of 78.6%. Our study suggested that the baseline ratio of EPO/ret.count should be used as an indicator for a favourable response to rhEPO therapy.

Recombinant Human Erythropoietin as an Alternative to Blood Transfusion in Cancer-Related Anaemia

As physicians become more aware of the need to treat anaemia in their patients with cancer, they have to consider 2 treatment options: red blood cell transfusion or recombinant human erythropoietin [epoetin alfa; epoetin beta]. Healthcare systems are under increasing pressure to lower costs while maintaining quality of care; therefore, treatment of cancer-related anaemia requires a disease management strategy aimed at achieving optimal clinical and economic outcomes. Although blood transfusion is the traditional and fastest means of alleviating associated symptoms, possible complications include acute transfusion reactions, transfusion-related acute lung injury and bacteraemia. Long term complications comprise transmission of viruses and prions, alloimmunisation, immunomodulation and graft-versus-host disease. Despite the introduction of additional screening and sterilisation procedures, transfusions cannot be considered as completely safe, especially with the emergence of new infectious agents. Moreover, the clinical significance of a possible effect on immunocompetence, in terms of promoting tumour growth and risk of infection, remains to be resolved. Treatment with recombinant human erythropoietin increases haemoglobin levels and reduces the need for transfusion in patients with cancer-related anaemia. Trial data also show that recombinant human erythropoietin therapy is well tolerated by patients, and is useful in preventing and treating anaemia induced by cancer treatment.

Consensus statement: Anemia in HIV infection—current trends, treatment options, and practice strategies

Background Despite important advances in antiretroviral therapy, anemia remains a problem in many HIV-infected patients. Although the incidence of anemia in these patients has decreased, its prevalence appears to have stabilized or decreased only slightly. Anemia has a deleterious effect on both functional capacity and quality of life, and has been associated with shortened survival. Objective The Anemia in HIV Working Group, an expert panel of physicians and researchers involved in the care of HIV-infected patients, met to determine the impact of anemia in this patient population; to develop practice strategies for the clinician treating HIV-infected patients with anemia; and to identify future research directions. Methods The proposed practice strategies are based on results of the available clinical trials (as identified through a MEDLINE ® search), a review of the literature, and the clinical experience and expert opinion of the panel. The present report is based on meetings held in February and June of 1998; as further experience with various treatment options accumulates and the impact of highly active antiretroviral therapy becomes clearer, the panel will reconvene to develop evidence-based guidelines. Results The working group considers HIV-associated anemia to be an important contributor to the morbidity and mortality of this infection. Recent reports indicate that recovery from anemia is associated with improved quality of life and survival. Conclusions As HIV-infected persons live longer, maintaining quality of life becomes an increasingly important goal of treatment. When planning treatment strategies, clinicians should consider the quality-of-life decrement caused by anemia. Transfusions should be used when rapid recovery is required, and underlying conditions causing anemia should be treated, if possible. Recombinant human erythropoietin (rHuEPO) therapy is appropriate in certain HIV-infected persons and should be considered to maintain hemoglobin concentrations. The target hemoglobin level is 12 g/dL for men and 11 g/dL for women. Weekly rHuEPO dosing is suggested, initiated at 40,000 U, as has been established in patients with cancer.

Erythropoietin, iron, and erythropoiesis

Recent knowledge gained regarding the relationship between erythropoietin, iron, and erythropoiesis in patients with blood loss anemia, with or without recombinant human erythropoietin therapy, has implications for patient management. Under conditions of significant blood loss, erythropoietin therapy, or both, iron-restricted erythropoiesis is evident, even in the presence of storage iron and iron oral supplementation. Intravenous iron therapy in renal dialysis patients undergoing erythropoietin therapy can produce hematologic responses with serum ferritin levels up to 400 μg/L, indicating that traditional biochemical markers of storage iron in patients with anemia caused by chronic disease are unhelpful in the assessment of iron status. Newer measurements of erythrocyte and reticulocyte indices using automated counters show promise in the evaluation of iron-restricted erythropoiesis. Assays for serum erythropoietin and the transferrin receptor are valuable tools for clinical research, but their roles in routine clinical practice remain undefined. The availability of safer intravenous iron preparations allows for carefully controlled studies of their value in patients undergoing erythropoietin therapy or experiencing blood loss, or both.

Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity

Anemic patients with chronic renal failure receiving recombinant human erythropoietin (rHuEPO) therapy frequently develop hypertension through an unknown mechanism. We hypothesize that EPO receptors (EPORs) on endothelial cells (ECs) in various sites of vasculature may mediate the activities of nitric oxide synthase (NOS) and/or the release of endothelin-1 (ET-1), contributing to blood pressure changes. We tested this hypothesis using primary cultures of ECs obtained from human coronary artery (HCAEC), pulmonary artery (HPAEC), dermis (HDEC), and umbilical vein (HUVEC). EPORs were measured by 125I-EPO binding. The effect of EPO on EPOR, ET-1, and NOS mRNA levels was assessed by quantitative reverse transcription-polymerase chain reaction. Cellular NOS activity and ET-1 release into the medium was measured by the NOSdetect assay and by radioimmunoassay kits. Short-term (4 h) treatment with EPO (4 U/mL) did not change the number or affinity of EPOR per cell. Neither were there any changes in the amount of EPOR, ET-1, and NOS transcripts (cDNA/microg of mRNA) nor in ET-1 release and NOS activity. In HUVEC only, 24-hour exposure to EPO caused a threefold increase in NOS transcript. In other cells, EPO treatment for six days increased NOS activity by twofold to fourfold. We show that upon extended exposure, EPO induces NOS activity but does not affect ET-1 release. These findings indicate that the hypertensive effect of EPO is not likely to be caused by a direct effect on ECs.

Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure

The optimal target hematocrit (Ht) level in recombinant human erythropoietin (rHuEPO) therapy remains controversial and has hardly been investigated in predialysis patients. We prospectively studied the regression of left ventricular hypertrophy (LVH) on echocardiography in nine predialysis patients with chronic renal failure after a partial correction (target Ht, 30%) and normalization (target Ht, 40%) of the Ht with rHuEPO treatment. Twenty-four-hour ambulatory blood pressure monitoring was also performed. The administration of rHuEPO significantly increased Ht to the target values. The rate of renal failure progression did not change during rHuEPO treatment for 12 months (Cr, from 6.2 ± 2.0 to 5.5 ± 2.1 mg/dL). The left ventricular mass index (LVMI) tended to decrease after a partial correction of anemia (Ht, 32.1% ± 1.8%) at 4 months, whereas it tended to significantly decrease after normalization of Ht (Ht, 39.1% ± 2.4%) at 12 months (baseline, 140.6 ± 12.1 g/m2; partial correction, 126.9 ± 10.0 g/m2; normalization, 111.2 ± 8.3 g/m2). All patients had received antihypertensive medication before rHuEPO administration, and additional drugs were also required in four cases during the study. As a result, a good overall blood pressure control was obtained without any adverse effects on the circadian blood pressure rhythm. In conclusion, from the perspective of LVH regression, the normalization of Ht was found to be more effective than that associated with a partial correction of anemia during rHuEPO therapy.

Reticulocyte Cellular Indices: A New Approach in the Diagnosis of Anemias and Monitoring of Erythropoietic Function

Reticulocyte analysis has been extended from the simple enumeration of reticulocytes to precise measurements of mRNA content and of cellular indices such as volume, hemoglobin (Hb) concentration, and content. Assessment of reticulocyte maturity is based on the fluorescence intensity of reticulocytes, which depends on RNA content. The appearance of high fluorescence reticulocytes has been shown to be associated with engraft-ment in the setting of bone marrow or peripheral stem cells transplantation, although it is still not clear how this parameter can improve quality or cost of care compared with the traditional use of absolute neutrophil counts. Reticulocyte indices have been studied especially in the setting of iron deficiency and functional iron deficiency during recombinant human erythropoietin (r-HuEPO) therapy. Reticulocyte hemoglobin content (CHr) may allow prompt identification of an imbalance between r-HuEPO therapy and iron availability by detecting the presence in reticulocytes of iron-restricted erythropoiesis. Diagnosis of simple iron deficiency can also be achieved in a more cost-effective fashion by using CHr in conjunction with the regular complete blood count (CBC), rather than relying on the traditional biochemical parameters of iron metabolism. Response to therapy of megaloblastic anemia can also be monitored with CHr. These new reticulocyte parameters provide a real-time assessment of the functional state of erythropoiesis.

Stimulation of tumour necrosis factor-alpha production by recombinant human erythropoietin may contribute to failure of therapy.

Although the mechanism of unresponsiveness to recombinant human erythropoietin therapy in dialysis patients has been studied extensively in recent years, many aspects remain unclear. We previously found that administration of erythropoietin induces interleukin-1beta, a cytokine that inhibits erythropoiesis. The present study investigated the involvement of tumour necrosis factor-alpha, another cytokine which inhibits erythropoiesis. Peripheral blood mononuclear cells were obtained from 18 patients on continuous ambulatory peritoneal dialysis, who were being treated with erythropoietin for renal anaemia, and were cultured with various concentrations of erythropoietin (0, 1, 5, 10, and 50 U/ml). Then the tumour necrosis factor-alpha level in the culture supernatant was assayed. The 18 patients were divided into four groups on the basis of the haematocrit after treatment: group A (n = 3), <23.0%; group B (n = 5), 23.0-24.9%; group C (n = 7), 25.0-26.9%; and group D (n = 3), > or =27.0%. In group A, the tumour necrosis factor-alpha level in the culture supernatant was increased by incubation with erythropoietin, while it was not increased in other groups. The tumour necrosis factor-alpha level was significantly higher in group A than in the other groups at erythropoietin concentrations of 5 U/ml. These results suggested that induction of tumour necrosis factor-alpha is one of the reasons for unresponsiveness to recombinant human erythropoietin.

A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study).

End-stage renal disease (ESRD) is commonly associated with complaints of disturbed sleep and sleep disorders, frequently related to periodic limb movements in sleep (PLMS) or sleep apnea that may result in daytime sleepiness and other sequelae. Improvements in quality of life, including subjective sleep quality, have been reported in ESRD patients treated with recombinant human erythropoietin (rHuEPO). We investigated the objective effects of normalizing hematocrit on sleep disorders, sleep patterns, and daytime ability to remain awake in ESRD patients. Ten hemodialysis patients with sleep complaints while on rHuEPO therapy were studied by polysomnography while moderately anemic (mean hematocrit, 32.3%) and again when hematocrit was normalized (mean hematocrit, 42.3%) by increased rHuEPO dosing. Sleep patterns and associated parameters were monitored. Delivered dialysis dose and iron storage factors were monitored. Maintenance of Wakefulness Testing (MWT) was performed to assess daytime alertness/sleepiness. All 10 subjects experienced highly statistically significant reductions in the total number of arousing PLMS (P = 0.002). Nine of 10 subjects showed reductions in both the Arousing PLMS Index (P < 0.01) and the PLMS Index (P = 0.03) when hematocrit was normalized. Measures of sleep quality showed trends to improved quality of sleep. MWT demonstrated significant improvement in the length of time patients were able to remain awake (9.7 versus 17.1 minutes; P = 0.04). RHuEPO therapy with full correction of anemia reduces PLMS, arousals from sleep, and sleep fragmentation while allowing for more restorative sleep and improved daytime alertness. These findings may explain one mechanism for the improved quality-of-life parameters reported in ESRD patients treated with rHuEPO.

Relationship between erythropoietin and chronic heart failure in patients on chronic hemodialysis.

In the present study, the relationship between the blood erythropoietin level and cardiac function was investigated in 15 patients on chronic hemodialysis who developed chronic heart failure. Another 45 patients without cardiac dysfunction were selected as a control group that was matched for gender, age, and the duration of dialysis. The erythropoietin level was 256.3 +/- 481.8 mU/ml in the heart failure group, which was significantly higher than that in the control group (17.0 +/- 10.0 mU/ml, P < 0.01). Eight of the 15 patients in the heart failure group maintained a hematocrit of more than 30% without receiving recombinant human erythropoietin therapy, whereas 29 of the 45 patients in the control group required erythropoietin. In the heart failure group, the erythropoietin level was significantly correlated with the levels of atrial natriuretic peptide and brain natriuretic peptide (P < 0.01). These results suggest that heart failure can increase the erythropoietin level in proportion to the severity of cardiac dysfunction, even in patients on long-term dialysis.

Iron and infection: Clinical experience

Bacterial infection is a significant cause of morbidity and mortality in hemodialysis patients, and a number of studies have implicated iron overload as a risk factor for bacterial infection in these patients. While the underlying cause of increased susceptibility to bacterial infection is not completely understood, evidence suggests that iron overload alters the chemotactic and phagocytic properties of neutrophils, thereby reducing their ability to kill invading pathogens. T-cell function also appears to be altered. In addition, high levels of serum iron may promote replication and dissemination of bacterial pathogens that use iron as a growth factor. With the introduction of recombinant human erythropoietin therapy for hemodialysis patients, the need for red blood cell transfusions has been reduced and iron overload occurs much less frequently. Several recent studies have indicated that iron overload, which is suspected in the presence of high serum ferritin levels, may no longer be a significant risk factor for infection in hemodialysis patients receiving erythropoietin therapy. Major risk factors for infection in these patients include history of bacterial infection, immunosuppressive therapy, and vascular access via catheters rather than by arteriovenous fistula. In addition, anemia has recently been linked to an increased incidence of bacterial infection, particularly in patients receiving erythropoietin therapy. Therefore, repletion of iron stores and maintenance of iron balance without iron overload may prove to be important factors in reducing the incidence of bacterial infections in hemodialysis patients. However, the relationships between iron levels, anemia, and susceptibility to bacterial infection require further investigation. Am J Kidney Dis 34:s30-s34, 1999. Copyright © 1999 by National Kidney Foundation

Erythropoietin impairs endothelium-dependent vasorelaxation through cyclooxygenase-dependent mechanisms in humans

Hypertension is a major complication of recombinant human erythropoietin therapy in patients with end-stage renal disease. Although the mechanisms for this pressor effect remain unknown, in vitro and ex vivo experiments suggest that erythropoietin stimulates release of cyclooxygenase-dependent endothelium-derived contracting factors (EDCFs) and attenuates endothelium-dependent vasorelaxation. To investigate the effect of erythropoietin on human endothelial function, we measured forearm blood flow by strain gauge plethysmography before and after intraarterial incremental administration of erythropoietin (10 to 300 IU/min, total 3000 U), while infusing acetylcholine (4 to 24 μg/min) and sodium nitroprusside (0.2 to 1.2 μg/min) in healthy male volunteers (n = 12). To examine a possible role of EDCFs, we repeated the same protocol under the pretreatment with oral indomethacin (50 mg), a cyclooxygenase inhibitor (n = 8). Infusion of erythropoietin into the brachial artery increased the erythropoietin blood concentration of venous effluents significantly ( P < .0001) without changes in blood pressure and basal forearm blood flow. Acetylcholine and sodium nitroprusside increased forearm blood flow dose dependently before and after erythropoietin administration. However, acetylcholine-induced vasodilation (endothelium dependent) was significantly attenuated ( P < .001) after erythropoietin administration, whereas vasodilation to sodium nitroprusside (endothelium independent) was unchanged. After indomethacin pretreatment, erythropoietin no longer attenuated endothelium-dependent vasorelaxation. Our results indicate that erythropoietin may impair endothelial function acutely, probably through cyclooxygenase-dependent EDCFs in humans. Long-term effects of erythropoietin on endothelial function in uremic patients remain to be elucidated.

The effect of erythropoietin (rh-EPO) om in vitro proliferation of granulocyte/monocyte-determined stem cells in bone marrow and peripheral blood

The aim of the investigation was to determine the effect of recombinant human erythropoietin (rh-EPO) therapy on in-vitro proliferation of granulocyte/monocyte(gm)-determined stem cells in bone marrow and peripheral blood. The study comprised 28 dialysis patients (15 female, 13 male, aged between 22 and 78 years, dialysis sessions 3 times weekly 4 to 5 hours, mean duration time of dialysis treatment 4 to 99 months). Stem cell parameters were estimated before and after reaching the target hematocrit and the absolute number of leukocytes in peripheral blood was measured. No alteration in total leukocyte number (PMN, monocytes, lymphocytes) of peripheral blood was found. Dialysis patients had a diminished proliferation capacity of colony forming unit-granulocyte/monocyte (CFU-GM) in bone marrow and an increased one in peripheral blood. The CFU-GM proliferation capacity in bone marrow improved during rh-EPO (34.3 +/- 5.8 x 10(5)/ml vs 120.5 +/- 37.8 x 10(5)/ml), whereas no changes in peripheral blood could be observed (46.7 +/- 7.15 x 10(5)/ml vs 37.6 +/- 12.05 x 10(5)/ml).