rHuEPO Requirements Research Articles

Use of recombinant human erythropoietin in kidney transplant patients with stable graft function

The purpose of this work was to determine the necessity for rhuEPO for 50 kidney transplant patients with stable graft function. We analyzed the red cell series, blood pressure, renal function, anthropometric data of the donor and recipient, proteinuria, and relationship with other factors, including immunosuppressants, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The patients were divided into three groups depending on renal function: group A (with plasma creatinine <150 μmol/L), group B (151–250 μmol/L), and group C (>250 μmol/L). All patients were studied for 1 year. Erythropoietin use did not affect renal function, proteinuria or number of antihypertensive drugs group. The degree of renal dysfunction determined the time necessary to reach an adequate hemoglobin level (>12 g/L) and and the mean dose of weekly rhuEPO needed. The use of ACE inhibitors or ARBs increased the rhuEPO requirements in each group.

Adjunctive therapy in anaemia management.

Iron supplementation is essential for adequate response to recombinant human erythropoietin (rHuEPO) or darbepoetin alfa. Oral iron therapy is often ineffective as the quantity of iron absorbed after oral intake may be insufficient to keep pace with the demands of rHuEPO-stimulated erythropoiesis in patients with end-stage renal disease (ESRD). Currently available i.v. iron preparations include dextran, iron gluconate, and iron sucrose. As rare, but serious, adverse reactions to i.v. iron dextran have been reported, alternative preparations may be preferred. Careful monitoring of iron parameters is required to avoid the effects of over-treatment. Renal anaemia and iron therapy are associated with oxidative stress, leading to a shortening of the lifespan of red blood cells (RBC) and resistance to rHuEPO. rHuEPO therapy may also enhance oxidative stress on RBC. Oxidative stress can be attenuated or prevented by supplementation with vitamin E or melatonin. Vitamin E therapy has also been shown to have a rHuEPO-sparing effect. Disturbances of carnitine metabolism may contribute to the development of renal anaemia in ESRD patients. Oral or i.v. L-carnitine therapy results in an increase in haematocrit and a significant decrease in rHuEPO requirement in HD patients. As yet, there is no general recommendation for L-carnitine supplementation for ESRD patients with renal anaemia.

Insulin-Like Growth Factor System Components in Relation to Erythropoietin Therapy and Bone Metabolism in Dialyzed Patients and Kidney Transplant Recipients

Insulin-like growth factor (IGF) system components appear to be the most important regulators of bone cell function. On the other hand, IGF-1 is shown to be an important regulator for erythropoiesis. The aim of the study was to examine the relationships between IGF system, requirements of erythropoietin, endogeneous erythropoietin levels, bone metabolism assesed by biochemical markers, markers of nutrition such as cholesterol and albumin in recombinant human erythropoietin (rHuEPO)-treated patients maintained on chronic hemodialyses or peritoneal dialyses as well as in kidney transplant recipients. The studies were performed on 79 chronically hemodialyzed patients; 28 of them did not receive rHuEPO, 51 subjects received rHuEPO, 34 patients on continuous ambulatory peritoneal dialysis (CAPD), 16 of them did not receive rHuEPO, 18 were given rHuEPO and 46 kidney allograft recipients. Endogeneous erythropoietin concentration, bone-specific alkaline phosphatase and serum CrossLaps were assayed by ELISA. Intact PTH, osteocalcin, 1,25-(OH)₂ D₃, 25-OH D₃, IGF-1, procollagen type I carboxy-terminal extension peptide (PICP) and procollagen type I cross-linked carboxy-terminal telopeptide (ICTP) were studied by RIA, whereas IGFBP-1 and IGFBP-3 concentrations were assayed by IRMA. We found a significantly higher IGF-1 and IGFBP-3 in rHuEPO-treated HD patients when compared to CAPD subjects given rHuEPO as well as to hemodialysis (HD) patients not treated with rHuEPO. IGF-1 was significantly higher in kidney transplant recipients when compared to dialyzed patients without rHuEPO therapy. IGFBP-1 was similar in all groups of patients (including kidney transplant recipients) studied. In CAPD patients not given rHuEPO concentrations of ICTP and PICP were significantly lower when compared to rHuEPO-treated CAPD subjects and HD patients not receiving rHuEPO therapy. Serum CrossLaps in CAPD patients treated with rHuEPO were significantly higher when compared to CAPD subjects without rHuEPO treatment and to kidney transplant recipients. In rHuEPO-treated CAPD subjects IGF-1 and IGFBP-1 correlated positively with serum CrossLaps (r = 0.61, p < 0.05 and r = 0.64, p < 0.05, respectively), whereas in hemodialyzed patients without rHuEPO a significant negative correlation between IGFBP-3 and serum CrossLaps was found (r = –0.69, p < 0.001) as well as between IGFBP-3 and aluminium (r = 0.51, p < 0.05), IGF-1 and ICTP (r = –0.43, p < 0.05). In conclusion, our data indicate a probable functional relationship between IGF system components, erythropoietin treatment in dialyzed patients and bone metabolism in renal replacement therapy in a form of hemodialyses, peritoneal dialyses and kidney transplantation. Dialyzed patients exhibit more pronounced renal osteodystrophy than kidney allograft recipients. IGF system components are influenced by erythropoietin therapy, but are not related to serum erythropoietin levels and rHuEPO requirements.

Efficacy of a Low-Dose Intravenous Iron Sucrose Regimen in Peritoneal Dialysis Patients

Sufficient iron substitution leads to a decrease in the required recombinant human erythropoietin (rHuEPO) dose and/or an increased hematocrit in dialysis patients. Intravenous (i.v.) application of larger doses of iron sucrose may be associated with hyperferritinemia, appearance of catalytically free iron, and impaired phagocyte function. Therefore, we investigated the effectiveness of a low-dose i.v. iron regimen in peritoneal dialysis (PD) patients. Forty-five PD patients were followed over a period of 1 year. Serum ferritin, serum transferrin saturation, and hemoglobin were measured monthly. In cases of absolute iron deficiency (serum ferritin < 100 microg/L), 50 mg iron sucrose was given i.v. every second week. In cases of functional iron deficiency (ferritin > or = 100 microg/L and transferrin saturation < 20%) and in iron repleted patients (ferritin > or = 100 microg/L and transferrin saturation > or = 20%), 50 mg i.v. iron sucrose was applied monthly. Iron therapy was stopped in cases of acute infection (until complete recovery) and when serum ferritin level was > or = 600 microg/L. To analyze the influence of iron substitution on erythropoiesis and rHuEPO requirements, the EPO resistance index (ERI; quotient of rHuEPO dose in units/kilogram/week and hemoglobin in grams per deciliter) was calculated every 3 months. The ERI decreased significantly during the course of the study in the whole patient group (p = 0.009) as well as in the subgroup of 21 patients with absolute iron deficiency (p = 0.01). A nonsignificant decrease in the ERI was observed within the group of 14 iron repleted patients (p = 0.5). There was no significant change in the ERI in 10 patients with functional iron deficiency (p = 0.6). The low-dose i.v. iron regimen used in this study substantially decreased rHuEPO requirements in patients with absolute iron deficiency and was effective in maintaining iron stores in iron repleted patients. However, in the absence of significant hyperparathyroidism, aluminum toxicity, or inadequate dialysis, it did not improve the ERI in 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.

Incidence of Peritonitis in Chronic Peritoneal Dialysis Patients Infused with Intravenous Iron Dextran

The Dialysis Outcomes Quality Initiative (DOQI) guidelines, published in 1997, emphasize the need for careful monitoring of iron stores and for provision of adequate iron replacement therapy to achieve target goals of hemoglobin concentration in end-stage renal disease (ESRD) patients, especially those treated with recombinant erythropoietin (rHuEPO). Intravenous iron dextran (IVID) therapy, which has long been used in hemodialysis patients, is increasingly being used in chronic peritoneal dialysis (CPD) patients. In 1997, we began using this form of iron therapy for our CPD patients. However, because considerable data exists to show a relationship between iron metabolism and acute infections, we questioned whether IVID infusion placed our patients at greater risk for peritonitis, the leading cause of death and patient drop-out from CPD therapy. To evaluate the relationship between iron and infection, we studied episodes of peritonitis in CPD patients who were infused with IVID. In a retrospective study of adult CPD patients who received IVID during 1998, we investigated the occurrence of peritonitis episodes and the spectrum of causative organisms. Patients with a hemoglobin level of < 12.5 g/dL who also had a ferritin level < 100 ng/mL or a transferrin saturation level < 20% (or both) and who did not respond to oral iron therapy, were administered between 0.5 g and 1.0 g of IVID in an outpatient hospital setting. We calculated the expected and observed number of peritonitis episodes in these patients within 30, 60, and 90 days after infusion of IVID. During the study period, 56 patients received 77 doses of IVID, with 14 patients requiring 2 or more infusions. Of the 77 doses, 71 were given as a 1-g bolus. The IVID was well tolerated by all patients. Within 90 days of IVID administration, 14 patients developed peritonitis: 6 episodes occurred within 30 days, 7 episodes occurred between 31 and 60 days, and 1 episode occurred between 61 and 90 days after the IVID dosing. The peritonitis rate for patients not receiving IVID was 1 episode per 13.7 patient-months. Taking this rate as the "expected" rate, the expected number of episodes of peritonitis for the study population was 5.6 episodes within 30 days, 11.2 episodes within 60 days, and 16.8 episodes within 90 days following IVID administration. The difference between the expected and observed rates of peritonitis in patients who were dosed with IVID was not statistically different. The spectrum of organisms seen in the peritonitis episodes in the study population was not significantly different from that seen in the peritonitis episodes in our CPD unit population. There is evidence that IVID infusion therapy can improve anemia and reduce rHuEPO requirements in CPD patients, usually without adverse reaction and without exposing patients to an increased risk of peritonitis. More research is needed in the area of potential increased risk of infection in ESRD patients who are (1) infused with large doses of IVID, and (2) iron-overloaded.

Leptin and Serum Erythropoietin in Hemodialyzed and Peritoneally Dialyzed Uremic Patients during rHuEPO Therapy

Leptin produced by fat cell has an unanticipated role in hematopoietic system development. We examined the relationships between leptinemia and requirements of erythropoietin (Epo), endogenous Epo levels as well as markers of inflammation: C-reactive protein, tumor necrosis factor α (TNFα) and interleukin-1 (IL-1) in rHuEPO-treated patients maintained on chronic hemodialyses or peritoneal dialyses. The studies were performed on 51 chronically hemodialyzed patients, 20 of them did not receive rHuEPO, 31 subjects received rHuEPO, and 22 patients on CAPD, 13 of them did not receive rHuEPO, 9 subjects were given rHuEPO. In hemodialyzed patients (Epo and Non-Epo group) leptin levels were significantly higher when compared to CAPD patients (Epo and Non-Epo group, respectively). Leptin in peritoneal fluid was significantly higher in the Non-Epo group. In ultrafiltrate, leptin levels were below the detection limit of 0.5 ng/ml. Epo levels in the HD + Epo group were significantly lower than in the HD + Non-Epo group and CAPD + Epo group. TNFα and IL-1 concentrations were significantly lower in both groups of CAPD patients when compared to respective HD groups. Treatment with rHuEPO resulted in nonsignificant decline in serum leptin (p = 0.07 in HD and p = 0.08 in CAPD) and significant leptin loss in peritoneal fluid. It may be of clinical relevance in dialyzed patients. In both groups of Epo-treated patients, positive physiological correlation between leptinemia and BMI disappeared. Leptin levels do not correlate with rHuEPO requirements and serum Epo in dialyzed patients.

Low Dose Desferrioxamine Can Improve Erythropoiesis in Iron-Overload Hemodialysis Patients Without Side Effects

Objective: Multiple blood transfusions were often required to treat anemia in uremia patients before the era of recombinant human erythropoietin (r-HuEPO). Iron overload thus frequently occurred in chronic hemodialysis patients. Desferrioxamine (DFO) is an effective chelating agent, which can remove excessive iron and can enhance erythropoiesis. Large dose DFO treatment is a therapy associated with the development of severe complications. In this study, a low dose DFO regime was used to treat iron overloaded hemodialysis patients. The efficacy and side effects of this regiment were evaluated.Materials and Methods: Eight iron overloaded chronic hemodialysis patients were enrolled in this study. All patients received DFO 500 mg intravenously twice-a-week for eight months. Serum aluminum, transferrin saturation (TFS) and r-HuEPO requirement were recorded before and after DFO treatment. Serum ferritin and hematocrit (Hct) were measured before, during, and after the DFO withdrawal period. All patients were evaluated and followed closely during treatment.Results: Changes in aluminum, TFS and r-HuEPO dosage were unremarkable (p > 0.05). Hct increased significantly after eight months of DFO treatment (from 25.3% to 27.0%, p < 0.05), Ferritin level was reduced by 43.2% at the end of treatment and an evident decline of ferritin was achieved after four months of treatment (2102 ng/mL to 1166 ng/mL, p < 0.05). All patients tolerated the treatment well and no complications were foundConclusion: Low dose DFO can chelate iron effectively in chronic hemodialysis patients. This treatment can enhance erythropoiesis without adverse effects

The required dose of erythropoietin during renal anaemia treatment is related to the degree of impairment in erythrocyte deformability.

Renal anaemia is rapidly corrected by recombinant human erythropoietin (rHuEpo) therapy, but the dose required varies greatly. Since impaired erythrocyte deformability may be one factor contributing to the development of renal anaemia, the interrelationship between that variable and the rHuEpo requirement was examined. Twenty-five patients treated with hemodialysis and rHuEpo for at least 6 months were included in the study. The Hb value had been stable and the rHuEpo dose unchanged the last two months. Using a rotational viscometer, the fluidity of erythrocytes, separated from plasma and re-suspended in isotonic buffered saline to a standardized haematocrit, was taken as a measure of erythrocyte deformability. The average weekly dose of s.c. epoetin alpha was 186 +/- 93 U/kg body weight (range 56-370). The dose was correlated to the reticulocyte fraction (R = 0.69, P = 0.0001). When the rHuEpo dose was used as dependent variable and blood haemoglobin concentration, serum (S) albumin, S ferritin, S aluminium, S PTH, S urea, Kt/V/week, erythrocyte fluidity, and plasma viscosity were used as independent variables in a stepwise multiple regression analysis, only erythrocyte fluidity remained significantly negatively correlated to the rHuEpo dose (R = 0.5, P = 0.01). Despite a tendency towards higher doses of rHuEpo in patients with a C-reactive protein concentration exceeding 20 mg/l, the Hb was lower in these patients. We conclude that the interindividual differences in bone marrow response to rHuEpo were small in these patients. Impaired erythrocyte deformability and inflammation seem to be factors associated with increased rHuEpo requirement.

L-Carnitine effects on anemia in hemodialyzed patients treated with erythropoietin

To demonstrate whether l-carnitine treatment could further improve the anemia in dialyzed patients under recombinant human erythropoietin (r-HuEPO) therapy, leading to a reduction in r-HuEPO requirements, l-carnitine (1 g intravenously after every dialysis session) was administered for 6 months to a group of 13 patients; the results were compared with data from a placebo control group (N = 11). Globular osmotic fragility and endogenous EPO secretion were also evaluated. l-Carnitine treatment promoted a 38.1% reduction in r-HuEPO requirements in the active group (102.2 ± 52.6 U/kg/wk v 63.3 ± 37.8 U/kg/wk; P < 0.02), with globular osmotic fragility and endogenous EPO levels remaining unchanged and thus not accounting for carnitine effect on anemia. In the active group, seven patients decreased r-HuEPO needs (responders), while six did not (nonresponders). Compared with nonresponders, responders showed higher mean values at time 0 for r-HuEPO requirements and endogenous plasma EPO levels, although not statistically significant. It is concluded that l-carnitine deficiency might promote EPO resistance in dialyzed patients, which is corrected by l-carnitine supplementation, ultimately reducing r-HuEPO requirements.

Importance of iron supply for erythropoietin therapy

rHuEpo and iron therapy corrects renal anaemia. However, dosage, route of administration, and monitoring of iron and rHuEpo therapy in uraemic patients remains controversial. Therefore a 22-month i.v. iron substitution trial, subdivided into four study periods, was initiated in 64 iron-depleted chronic haemodialysis (HD) patients receiving i.v. rHuEpo therapy. Within the first period (6 months) patients were treated with high-dose iron (100 mg at the end of HD treatment, mean cumulative i.v. iron saccharate dosage was 2538 +/- 810 mg per patient) in order to replete the iron stores. During the 2nd period (6 months) the available iron pool was maintained with low-dose iron by administration of 10, 20, or 40 mg iron at each HD, depending on haemoglobin, serum ferritin and transferrin saturation levels. During the 3rd period (4 months), the iron-replete patients were randomized to i.v. or s.c. route of rHuEpo administration. During the 4th period (3 months) iron substitution was omitted to exclude severe iron overload. In the first study period, high-dose iron therapy dramatically reduced the weekly rHuEpo requirement by 70% of the initial dose (from 217 +/- 179 to 62.6 +/- 70.2 U/kg/week). In the 2nd period iron storage pools were easily maintained. Serum ferritin and transferrin saturation levels remained stable during this study period. Randomization for thrice-weekly i.v. or s.c. administration of rHuEpo in the 3rd study period revealed comparable efficacy for both administration routes in iron-replete patients. In well-nourished patients (serum albumin > 40 g/l) without hyperparathyroidism (parathyroid hormone levels < 100 pg/ml), 50-60 U/kg/week rHuEpo were required in contrast to > 100 U/kg/week in patients with hyperparathyroidism. In the 4th study period, withdrawal of iron administration led to a rapid decrease of serum ferritin and transferrin saturation levels, indicating the absence of severe iron overload. Long-term thrice-weekly i.v. low-dose iron therapy (10-20 mg per HD treatment) proved to be a very effective, economical and safe treatment schedule for iron-replete HD patients. Intravenous and s.c. rHuEpo therapy was equally efficacious in iron-replete, well-nourished patients. HD patients with increased parathyroid hormone levels require significantly more rHuEpo than HD patients with parathyroid hormone levels values < 100 pg/ml).

Continuous Ambulatory Peritoneal Dialysis in End-Stage Renal Disease Due to Multiple Myeloma

To evaluate (1) the disease course, (2) the response to recombinant human erythropoietin (rHuEPO), and (3) the morbidity and mortality of patients with end-stage renal disease (ESRD) due to multiple myeloma (MM) who were treated with continuous ambulatory peritoneal dialysis (CAPD) DESIGN: Retrospective study. Tertiary teaching hospital--The Toronto Hospital, Toronto, Ontario, Canada. Seven patients with ESRD due to MM who were treated with CAPD. Mean age of the patients was 77.2 years (median 80 years, range 65-88 years). Two were in stage IB, 1 was in stage IIB, and the remaining 4 were in stage IIIB, according to Durie and Salmon's staging. Three patients received rHuEPO; 2 of these also were receiving chemotherapy for myeloma. The mean rHuEPO requirement was 277 U/kg/wk, which was more than other ESRD patients' requirements. Mean duration of CAPD was 20.6 months (6-58 months). The peritonitis rate was one episode in 14.4 months. The frequency of hospitalization was once in 5.6 months, and the mean number of days spent in hospital was 20 days per year. Quality of life did not get worse and, if anything, improved marginally while they were on CAPD. Three patients died after a mean survival of 32.7 months, and the remaining 4 patients are still alive. Myeloma patients with ESRD do fairly well on CAPD without deterioration in their quality of life and with an acceptable peritonitis rate.

Continuous Ambulatory Peritoneal Dialysis in End-Stage Renal Disease Due to Multiple Myeloma

Objective To evaluate (1) the disease course, (2) the response to recombinant human erythropoietin (rHuEPO), and (3) the morbidity and mortality of patients with endstage renal disease (ESRO) dueto multiple myeloma (MM) who were treated with continuous ambulatory peritoneal dialysis (CAPO). Design Retrospective study. Setting Tertiary teaching hospital -The Toronto Hospital, Toronto, Ontario, Canada. Patients Seven patients with ESRO due to MM who were treated with CAPO. Results Mean age of the patients was 77.2 years (median 80 years, range 65 88 years). Two were in stage IB, 1 was in stage IIB, and the remaining 4 were in stage IIIB, according to Ourie and Salmon's staging. Three patients received rHuEPO; 2 of these also were receiving chemotherapy for myeloma. The mean rHuEPO requirement was 277 U/kglwk, which was more than other ESRO patients’ requirements. Mean duration of CAPO was 20.6 months (6 -58 months). The peritonitis rate was one episode in 14.4 months. The frequency of hospitalization was once in 5.6 months, and the mean number of days spent in hospital was 20 days per year. Quality of life did not get worse and, if anything, improved marginally while they were on CAPO. Three patients died after a mean survival of 32.7 months, and the remaining 4 patients are still alive. Conclusions Myeloma patients with ESRO do fairly well on CAPO without deterioration in their quality of life and with an acceptable peritonitis rate.