Anemia management in patients on peritoneal dialysis: efficacy and safety of epoetin delta

In a one-year, multicenter, open-label, uncontrolled trial, epoetin delta was given subcutaneously, 1-3-times weekly to peritoneal dialysis patients who had previously received an epoetin. Dose was adjusted to maintain hemoglobin at 10.0-12.0 g/dL. The primary endpoint was mean hemoglobin over weeks 12-24. Safety was assessed. Mean+/-SD baseline hemoglobin was 11.2+/-0.9 g/dL. Hemoglobin over weeks 12-24 was 11.6+/-1.1 g/dL. Adverse events were those expected in this patient population. No life-threatening adverse events occurred. Subcutaneous epoetin delta was effective and well tolerated for the treatment of anemia in peritoneal dialysis patients.     

Relationship between resistance to erythropoietin and high anomalous hemoglobin levels in hemodialysis patients with beta-thalassemia minor

In dialysis patients beta-thalassemia is a cause of resistance to erythropoietin (EPO). The aim of the present study is to evaluate the relationship between the amount of circulating anomalous hemoglobin chain and EPO resistance in hemodialysis. Ten hemodialyzed patients with beta-thalassemia minor were studied. The mean hemoglobin level was 9.22 +/- 0.91 g/dl, the HbA2 ranging between 5.6 and 6.8%; the weekly EPO dose was 13,500 +/- 7,185 IU/week and significantly correlated with HbA2 (r = 0.965; p = 0.0001). When stratifying patients in two groups according to HbA2 level (LOW <6%, n = 4; HIGH >6%, n = 6; HbA2 levels, respectively, 5.7 +/- 0.1 and 6.4 +/- 0.3 g/dl, p = 0.002), it was evidenced that the need of EPO was 13,200 +/- 3,033 IU/week in LOW and 36,167 +/- 13,060 IU/week in HIGH (p < 0.001). The EPO Resistance Index in the two groups was 13.4 +/- 4.1 IU/kg BW/week/g Hb in LOW and 21.9 +/- 10.0 in HIGH (p < 0.05). No differences were evidenced between the two groups regarding age, dialysis, body weight, serum levels of urea nitrogen, creatinine, albumin, C-reactive protein, aluminum, ferritin, transferrin and parathyroid hormone. In conclusion, in patients with beta-thalassemia minor on chronic hemodialysis, the amount of anomalous hemoglobin chain directly correlate with EPO dose, strongly indicating the magnitude of resistance to erythropoietin.     

Improvement of anemia in hemodialysis patients treated by hemodiafiltration with high-volume on-line-prepared substitution fluid

BACKGROUND: Hemodiafiltration (HDF) is associated with a lower incidence of neuropathy, carpal tunnel syndrome, joint pain, and partial correction of anemia. HDF with on-line-prepared substitution fluid (OL HDF), as compared with conventional hemodialysis, increases the treatment tolerance and, as compared with standard HDF, avoids storage problems and allows a higher substitution volume at low cost. METHODS: Thirty-two hemodialysis patients treated by OL HDF for at least 9 months were studied. Hemoglobin, hematocrit, iron metabolism, serum albumin, dialysis dose and dry body weight were determined under a settled condition with regular hemodialysis 3 months before the transfer to OL HDF. The same parameters were analyzed 3, 6 and 9 months after the beginning of the new treatment modality. RESULTS: During OL HDF, hemoglobin values significantly increased in patients without addition of recombinant human erythropoietin (rHuEPO): baseline vs. 6 months 11 +/- 1.7 vs. 12 +/- 1.8 g/dl (p < 0.01); baseline vs. 9 months 11 +/- 1.7 vs. 12 +/- 1.6 g/dl (p < 0.05). In patients on a maintenance dose of rhuEPO, this could be significantly reduced, while the target hemoglobin levels were maintained (10.6 +/- 0.9 g/dl): baseline 99.8 +/- 50.4 U/kg/week, 3rd month 76.2 +/- 43 U/kg/week, 6th month 64.3 +/- 37 U/kg/week, and 9th month 59.4 +/- 38.6 U/kg/week (p = 0.007, p = 0.0006, and p = 0.0007, respectively, vs. baseline). Iron metabolism, dialysis dose, dry body weight and serum albumin levels did not significantly change during the follow-up period. Further, a stability of the rHuEPO supplementation was observed in 14 patients followed up for 24 months. CONCLUSIONS: OL HDF influences anemia and rHuEPO dose. It allows considerable anemia correction in patients without rHuEPO treatment, while it significantly reduces rHuEPO doses in those on rHuEPO treatment as compared with standard hemodialysis. The rHuEPO costs are consequently reduced.     

Treatment of anemia with epoetin in kidney transplant recipients

The aim of this study was to analyze the prevalence and efficacy of renal anemia treated with epoetin in maintenance kidney transplant recipients in Slovenia. By the end of 2009, 107 out of 537 patients (19.9%) had been treated with epoetin. A cohort of 49 patients (45.8%) were analyzed in detail: 11 patients received epoetin alpha, 18 epoetin beta, 10 darbepoetin alpha, and 10 patients received methoxy polyethylene glycol-epoetin beta. The median epoetin dose was 0.36 μg/kg body weight per week. The median serum laboratory parameters were as follows: hemoglobin 120 g/L, hematocrit 0.36, ferritin 332 ng/mL, transferrin saturation 34%, serum creatinine 145 μmol/L, serum albumin 41 g/L, intact parathyroid hormone 79 ng/L, and C-reactive protein 3 mg/L. We concluded that the prevalence of renal anemia in kidney transplant recipients treated with epoetin was approximately 20%, and laboratory parameters suggested that the treatment of renal anemia in this study cohort was optimal.     

Effects of icodextrin on insulin resistance and adipocytokine profiles in patients on peritoneal dialysis

Icodextrin peritoneal dialysis solution reportedly benefits patients suffering from metabolic derangement due to glucose load from dialysate. However, the effects of icodextrin on insulin resistance and adipocytokine profile remain unclear. Subjects comprised 14 stable patients on peritoneal dialysis for >6 months. Their mean age was 57 +/- 11 years and the mean duration of peritoneal dialysis was 49 +/- 30 months. Patients were classified into groups according to the index of insulin resistance (index of homeostasis model assessment: HOMA-IR): Group A, HOMA-IR < 2.0 (n = 7); and Group B, HOMA-IR >or= 2.0 (n = 7). Glucose peritoneal dialysis solution was subsequently switched to icodextrin once daily during the night. Changes in HOMA-IR and adipocytokine profiles were examined after three months. The glucose absorption dose tended to decrease in both groups after icodextrin introduction, with significant reductions in Group B. No changes were seen in body mass index, fluid status, peritoneal dialysis dose, residual renal function or fasting plasma glucose levels in either group. Plasma insulin levels were unchanged in Group A, but decreased significantly in Group B. The index of insulin resistance was thus unchanged in Group A (from 1.4 +/- 0.4 to 1.5 +/- 0.8) and significantly decreased in Group B (from 5.9 +/- 2.2 to 3.2 +/- 0.6; P < 0.01). Regarding plasma adipocytokine profiles, no changes were found in plasma leptin, tissue necrosis factor-alpha or total plasminogen activator inhibitor-1 levels in either group. Plasma adiponectin levels were unchanged in Group A, but significantly increased in Group B. Icodextrin solution could ameliorate insulin resistance by decreasing insulin levels due to a reduction in the glucose load and an increase in plasma adiponectin levels.     

Subcutaneous compared with intravenous epoetin treatment in patients on hemodialysis: one center study

The use of epoetin has, in Europe, been restricted to the intravenous (i.v.) route in patients on hemodialysis. This study is aimed at investigating impacts of this change in policy. We retrospectively compared 45 hemodialysis patients treated with epoetin (alpha, beta) subcutaneously (subcutaneous [s.c.] period) for 12 months before and 12 months after changing the route from s.c. to i.v., and 38 patients of the i.v. period who underwent long-term, i.v. low-dose iron therapy (i.v. iron period) for 6 months. During the study period, the dose of epoetin increased in the i.v. period compared to the s.c. period by 6.4% (7379 +/- 3556 IU/week [median 7846] vs 6907 +/- 3842 IU/week [median 5846], respectively [NS]). During the i.v. iron period, patients began to receive regular i.v. iron. The postiron epoetin dose was 5923 +/- 4779 IU/week (median 4500). The dose was decreased in comparison with the s.c. and i.v. periods by 14.2% and 19.7%, respectively. Hemoglobin decreased in the i.v. period compared to the s.c. period (120.4 +/- 8.0 g/L vs 123.5 +/- 6.7 g/L [P < 0.01]), and increased in the i.v. iron period compared to the s.c. and i.v. periods ([126.5 +/- 9.9 g/L vs 123.5 +/- 6.7 [P < 0.01]), and vs 120.4 +/- 8.0 (P < 0.01)]. Changing the route of administration of epoetin required an insignificant increase in dosage. Regular low-dose iron improves the response to epoetin and lowers the dose of epoetin, even in cases when the intravenously administration route is used.     

Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study

BACKGROUND & AIMS: Combination therapy with interferon alpha (IFN-alpha) and ribavirin (RBV) or pegylated IFN-alpha (PEG-IFN-alpha)/RBV for chronic hepatitis C virus (HCV) infection often causes anemia, prompting RBV dose reduction/discontinuation. This study assessed whether epoetin alfa could maintain RBV dose, improve quality of life (QOL), and increase hemoglobin (Hb) in anemic HCV-infected patients. METHODS: HCV-infected patients (n = 185) on combination therapy who developed anemia (Hb < or = 12 g/dL) were randomized into a U. S. multicenter, placebo-controlled, clinical trial of epoetin alfa, 40,000 U subcutaneously, once weekly vs. matching placebo. The study design used an 8-week, double-blind phase (DBP) followed by an 8-week, open-label phase (OLP), in which placebo patients were crossed over to epoetin alfa. RESULTS: At the end of the DBP, RBV doses were maintained in 88% of patients receiving epoetin alfa vs. 60% of patients receiving placebo (P < 0.001). Mean QOL scores at the end of the DBP improved significantly on all domains of the Linear Analog Scale Assessment (LASA) and on 7 of the 8 domains of the Short Form-36, version 2 (SF-36v2). Mean Hb increased by 2.2 +/- 1.3 g/dL (epoetin alfa) and by 0.1 +/- 1.0 g/dL (placebo) in the DBP (P < 0.001). Similar results were demonstrated in patients who switched from placebo to epoetin alfa in the OLP. Epoetin alfa was well tolerated; the most common adverse effects were headache and nausea. CONCLUSIONS: Epoetin alfa maintained RBV dose and improved QOL and Hb in anemic HCV-infected patients receiving combination therapy.     

Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. A randomized, controlled trial

BACKGROUND: The optimum regimen of epoetin alfa for prevention of allogeneic blood transfusion is unknown. OBJECTIVE: To determine whether a modified regimen of epoetin alfa reduces allogeneic blood transfusion in patients undergoing hip arthroplasty. DESIGN: Randomized, double-blind, multicenter trial comparing two modified dose regimens of epoetin alfa with placebo. SETTING: 13 teaching hospitals and 4 community hospitals in Canada. PATIENTS: 201 patients undergoing primary hip arthroplasty who had a hemoglobin concentration of 98 to 137 g/L and did not predonate blood. INTERVENTION: Patients were assigned in a 3:5:5 ratio to receive four weekly doses of epoetin alfa, 40 000 U (high-dose; n = 44) or 20 000 U (low-dose; n = 79), or placebo (n = 78), starting 4 weeks before surgery. All patients received oral iron supplementation, 450 mg/d, for 42 or more days before surgery. MEASUREMENTS: The primary end point was allogeneic transfusion. Secondary end points were thromboembolic events and change in reticulocyte count and hemoglobin concentration. RESULTS: Both modified epoetin alfa regimens significantly reduced the need for allogeneic transfusion: Five (11.4%) patients in the high-dose group (P = 0.001) and 18 (22. 8%) patients in the low-dose group (P = 0.003) had transfusion, compared with 35 (44.9%) patients in the placebo group. The hematologic response was substantial in patients who received epoetin alfa. In the high-dose group, low-dose group, and placebo group, the preoperative increase in reticulocyte count was 58.8, 37. 0 and 1.8 x 10(9) cells/L (P < 0.001), respectively, and the increase in hemoglobin concentration was 19.5, 17.2, and 1.2 g/L (P < 0.001). The incidence of thromboembolic events did not differ among groups. CONCLUSIONS: Both modified epoetin alfa regimens were effective compared with placebo in reducing allogeneic transfusion in patients undergoing hip arthroplasty. Patients who received high-dose epoetin alfa had the lowest transfusion rate.     

Growth hormone, IGF-I and its binding proteins (IGFBP-1 and -3) in adult uraemic patients undergoing peritoneal dialysis and haemodialysis

OBJECTIVE: The GH/IGF axis is altered in chronic renal failure (CRF). CRF patients usually show normal or high serum concentrations of GH and IGF-I, whereas all IGF binding proteins (IGFBP-1 to -6), except IGFBP-5, considerably increase with declining renal function. The aims of the present study were to quantify serum concentrations of GH, IGF-I, IGFBP-1 and IGFBP-3 in a group of patients with CRF, and determine whether there were differences according to the type of dialysis, that is, peritoneal dialysis (PD) and haemodialysis (HD). DESIGN: A cross-sectional study in the setting of a dialysis unit of a general hospital. PATIENTS AND MEASUREMENTS: We studied 108 dialysis patients treated by PD (n = 54, 32 males and 22 females, mean age 61.0 +/- 1.4 years) or HD (n = 54, 31 males and 23 females, age 62.6 +/- 1.5 years). A group of 42 healthy subjects of similar age, sex and body mass index (BMI) served as the control group. Baseline serum concentrations of GH, insulin, IGF-I, IGFBP-1 and IGFBP-3 were measured in all patients and control subjects. RESULTS: Fasting serum concentrations of IGF-I and its binding proteins (IGFBP-1 and IGFBP-3) were significantly higher in dialysis patients than in subjects with normal renal function. IGF-I (248.9 +/- 23.4 vs. 205.5 +/- 15.5 micro g/l, NS), IGFBP-3 (5.6 +/- 0.4 vs. 5.5 +/- 0.2 mg/l, NS) and IGFBP-1 (36.1 +/- 5.9 vs. 44.1 +/- 6.5 micro g/l, NS) concentrations were similar in both groups of dialysis (PD vs. HD) patients. However, GH (2.3 +/- 0.3 vs. 1.1 +/- 0.1 micro g/l, P < 0.001) and insulin (40.4 +/- 4.5 vs. 30.1 +/- 3.1 micro U/ml, P < 0.05) levels were significantly higher in the PD group than in the HD group. Both groups of dialysis patients showed significantly higher levels of insulin than healthy subjects (14.7 +/- 1.9 micro U/ml, P < 0.0001 and P < 0.01 for PD and HD, respectively). In both groups of dialysis patients, IGF-I correlated inversely with IGFBP-1 (PD group r = -0.46, P = 0.0006; HD group r = -0.57, P = 0.0001) and directly with IGFBP-3 (PD group r = 0.44, P = 0.001; HD group r = 0.73, P = 0.001). No correlation between insulin and IGFBP-1 was found in any of the groups studied. CONCLUSIONS: These findings demonstrate that adult dialysis patients have elevated IGF-I, IGFBP-1 and IGFBP-3 serum concentrations compared with subjects with normal renal function. Only GH and insulin show statistically significant differences in relation to type of dialysis. Finally, the negative correlation between IGF-I and IGFBP-1 and the positive correlation between IGF-I and IGFBP-3 are maintained in both groups of adult dialysis patients.     

Efficacy of epoetin alfa administered every 2 weeks to maintain hemoglobin and quality of life in anemic HIV-infected patients

Anemia, a common hematological abnormality in HIV, contributes to decreased quality of life (QOL). This study assessed once-every-2-week epoetin alfa on maintaining QOL and hemoglobin (Hb) in anemic HIV-infected patients in a 24-week, open-label, multicenter study. HIV-infected patients (Hb < or =12 g/dl) received epoetin alfa 40,000 units subcutaneously once weekly, until reaching Hb > or =13 g/dl. Patients then entered a maintenance phase (MP), in which epoetin alfa was administered every other week or at longer intervals. The trial objectives were to determine if QOL, as measured by the Medical Outcomes Study-HIV (MOS-HIV) general health perceptions (GHP) domain and Hb, was maintained. Safety was also assessed. A total of 292 patients were enrolled (72% on HAART). Mean baseline laboratory values were Hb = 10.8 g/dl, CD4(+) count = 280 cells/microl, and HIV RNA = 51,867 copies/ml. In all, 81% of patients reached Hb > or =13 g/dl and 92% reached Hb > or =12 g/dl. QOL was maintained from the beginning (GHP = 44.2 points) to the end of MP (GHP = 43.4 points) with every other week or longer dosing. Mean Hb at the beginning of MP was 13.4 +/- 0.5 g/dl and was 12.8 +/- 1.4 g/dl at study end. Epoetin alfa was well tolerated; adverse events were consistent with those reported in previous studies of epoetin alfa in HIV-infected patients. Although the clinical approach tested in this study is not consistent with current prescribing recommendations, the results confirm the efficacy of prolonged dosing intervals (every 2-4 weeks) in maintaining optimal Hb levels and QOL in anemic HIV-infected patients.     

Low-dose subcutaneous erythropoietin in continuous ambulatory peritoneal dialysis

We evaluated changes in hematocrit in patients on continuous ambulatory peritoneal dialysis (CAPD) before and after the administration of erythropoietin (EPO). Thirty-five patients were evaluated at the beginning of treatment with CAPD and after an average of 3.5 years on CAPD; mean hematocrit (Hct) rose from 25.4 +/- 5.4% to 28.1 +/- 6.7% (P less than 0.001). In the period before EPO administration 11 patients required a total of 44 transfusions (one patient needed 23 transfusions). Fifteen patients were started on subcutaneous erythropoietin 3,000 units 3 times a week and were followed for a mean period of 6.3 months. Hct rose from 23.8 +/- 1.8% to 25.2 +/- 2.4% (P less than 0.01) within the first 2 weeks and up to 27.5 +/- 3.7% (P less than 0.01) in the fourth week. By the eighth week the target Hct (30 to 35%) was reached. During the next 5 months the EPO doses were adjusted to each patient's needs ranging between 2,000 U per week to 4,000 U 3 times per week. Mild hypertension was the only side effect seen in some of the patients. In conclusion low dose subcutaneous EPO is effective in managing the anemia of patients on CAPD with only minor side effects.     

Resistance index to epoetin alpha and to darbepoetin-alpha in chronic hemodialysis patients: a cohort study

The effectiveness of the erythropoietic response can be evaluated using the resistance index (RI) to erythropoietic agents (EA) that measures the relationship between the dose administered and the hemoglobin levels attained. In a hemodialysis population, the RI is associated with several clinical and biochemical parameters, such as albumin levels, C-reactive protein (CRP), body mass index (BMI) and Kt/V. This index therefore reflects an important group of parameters that indicate comorbidities and measures the effectiveness of the treatment received. A substantial proportion of chronic hemodialysis patients show a relative resistance to human recombinant erythropoietin (rHuEPO) and require high doses to reach hemoglobin levels above 11 g/dl. Darbepoetin alpha is a new erythropoietic agent with a longer half-life than rHuEPO and greater biological activity in vivo. Furthermore, it remains at clinically effective plasma levels for much longer than rHuEPO. This study evaluated the effect on RI of switching from epoetin alpha to darbepoetin alpha in hemodialysis patients requiring i.v. rHuEPO at either high ( >10,000 UI/w) or low ( <4,000 UI/w) doses, compared to a control group receiving epoetin alpha. Unlike the control group, both groups of patients who switched to darbepoetin alpha showed a reduction in RI and a progressive reduction in the dose required of darbepoetin alpha with respect to the equivalent dose at treatment conversion. In the group requiring high doses, darbepoetin alpha RI (DRI) at week 24 was a significant 23.9% lower than epoetin alpha RI (ERI) at conversion (week 0) (p <0.01). In the group requiring low doses, DRI at week 24 was 13.4% lower than the ERI at conversion (p = NS). In both control groups, ERI at week 24 was higher than ERI at week 0. All groups showed stable hemoglobin levels across the study, with mean levels between 11.5 and 13.3 g/dl. CRP at week 24 was significantly related to albumin levels (p <0.001). In conclusion, switching hemodialysis patients from epoetin alpha to darbepoetin alpha was associated with a significant improvement in RI in the group of patients with high doses of EA, which we consider to be an important indicator of the effectiveness and quality of the treatment administered.     

Periodontal Treatment Reduces Chronic Systemic Inflammation in Peritoneal Dialysis Patients

Chronic systemic inflammation, a non traditional risk factor of cardiovascular diseases, is associated with increasing mortality in chronic kidney disease, especially peritoneal dialysis patients. Periodontitis is a potential treatable source of systemic inflammation in peritoneal dialysis patients. Clinical periodontal status was evaluated in 32 stable chronic peritoneal dialysis patients by plaque index and periodontal disease index. Hematologic, blood chemical, nutritional, and dialysis‐related data as well as highly sensitive C‐reactive protein were analyzed before and after periodontal treatment. At baseline, high sensitive C‐reactive protein positively correlated with the clinical periodontal status (plaque index; r = 0.57, P < 0.01, periodontal disease index; r = 0.56, P < 0.01). After completion of periodontal therapy, clinical periodontal indexes were significantly lower and high sensitivity C‐reactive protein significantly decreased from 2.93 to 2.21 mg/L. Moreover, blood urea nitrogen increased from 47.33 to 51.8 mg/dL, reflecting nutritional status improvement. Erythropoietin dosage requirement decreased from 8000 to 6000 units/week while hemoglobin level was stable. Periodontitis is an important source of chronic systemic inflammation in peritoneal dialysis patients. Treatment of periodontal diseases can improve systemic inflammation, nutritional status and erythropoietin responsiveness in peritoneal dialysis patients.     

Management of disease-related anemia in patients with multiple myeloma or chronic lymphocytic leukemia: epoetin treatment recommendations

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients often develop anemia due to the disease process and effects from disease therapy. Blood transfusion, the established treatment, has an immediate effect in improving patients' hemoglobin levels. However, this effect is transient and transfusion is associated with several risks, including infections and mild to life-threatening immunologic reactions. A newer option is recombinant human erythropoietin (epoetin); a biological treatment that leads to increased hemoglobin levels over an extended time without the risks of blood transfusion. Extensive evidence has shown that epoetin is effective in the treatment of cancer-associated anemia. An international expert panel met to develop treatment recommendations for the use of epoetin in MM and CLL patients. Based on the available data, it is recommended that treatment be initiated only after other possible causes of anemia are eliminated. Epoetin should be administered to any patient with hemoglobin < or=10 g/dl. Patients with hemoglobin 10-12 g/dl should receive epoetin if they suffer from significant symptoms of anemia and/or have progressively decreasing hemoglobin values. Dosage should be initiated at 10 000 IU three times/week or 40 000 IU once/week and be titrated to maintain hemoglobin at 12 g/dl. Nonresponsive patients (<1 g/dl increase over four weeks) may have their dose increased to 20 000 IU three times/week or 60 000 IU once/week, respectively. Epoetin treatment should be discontinued if there is no response to the increased dosage, or hemoglobin >14 g/dl. Treatment should resume for patients who exceed 14 g/dl, at a reduced dosage, if their hemoglobin falls below 12 g/dl.     

Kinetics of reticulocyte maturity fractions and indices and iron status during therapy with epoetin beta (recombinant human erythropoietin) in cardiac surgery patients

We evaluated the changes in reticulocyte maturity fractions and indices, as measured by flow cytometry, during preoperative treatment with recombinant human erythropoietin (epoetin beta) in cardiac surgery patients. A total of 72 patients was enrolled in this double-blind, randomized, placebo-controlled clinical trial and assigned to the two treatment groups (5 × 500 U/kg bodyweight epoetin beta or placebo intravenously over 14 days preoperatively). Therapy with epoetin beta produced continuous increases in hematocrit/hemoglobin, in the most mature fraction of reticulocytes (LR), and in reticulocyte count. In the first treatment week there were parallel increases in the fraction of most immature reticulocytes (HR) and in the reticulocyte mean cell volume. During the second week of treatment the reticulocyte mean cell hemoglobin content (CHr) decreased, but CHr was independent of all iron parameters, affecting neither the reticulocyte fractions nor the hematocrit/hemoglobin increase. The total preoperative rise in hematocrit correlated with the rises in LR fraction (P = 0.0270) and reticulocyte count (P = 0.0486) during the first week of treatment. Whereas in the epoetin beta patients the preoperative change in HR fraction showed negative correlations with transferrin saturation at baseline (P = 0.0058) and with the preoperative change in iron (P = 0.0113), the preoperative change in the LR fraction correlated positively with transferrin at baseline (P = 0.0115). Postoperatively, the reticulocyte parameters revealed that the onset of increased stimulation of erythropoiesis did not occur in the placebo patients until the second postoperative day, whereas erythropoietic activity in the epoetin beta patients was much higher during the postoperative period as well, as a result of the preoperative stimulation of erythropoiesis. The reticulocyte parameters measured by flow cytometry permitted an objective analysis of erythropoietic activity during treatment with epoetin beta and in all patients postoperatively. Further studies in various types of epoetin beta therapy are needed in order to clarify the value of these reticulocyte parameters for identification of iron deficiency and optimization of epoetin beta treatment regimen. Am. J. Hematol. 55:89-96, 1997. © 1997 Wiley-Liss, Inc.     

Key role of insulin resistance in vascular injury among hemodialysis patients

Insulin resistance prevails not only among diabetic patients but also among hypertensive and obese patients. The relationship between insulin resistance and cardiovascular diseases was investigated in hemodialysis (HD) patients. Eighty-one maintenance HD patients were enrolled. The homeostasis model assessment of insulin resistance (HOMA-IR) method was used to assess insulin resistance. The relationship of HOMA-IR with cardiovascular and all-cause events was assessed. Compared with nondiabetic patients (n = 55), diabetic patients (n = 26) showed higher HOMA-IR (2.5 +/- 0.3 vs 1.4 +/- 0.2, P < .05), lower ankle-brachial pressure index (ABI, 0.85 +/- 0.09 vs 1.12 +/- 0.02, P < .01), and shorter HD duration (3 +/- 1 vs 9 +/- 1 years, P < .01), although their body mass index was similar (22.3 +/- 0.5 vs 21.5 +/- 0.4 kg/m(2)). Nondiabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 36) had lower HOMA-IR (1.2 +/- 0.2 vs 1.8 +/- 0.4, P < .05) and higher ABI (1.18 +/- 0.02 vs 1.02 +/- 0.05, P < .01) than those without (n = 17). Cardiovascular events were less common in HD patients with normal HOMA-IR (P < .05) or ABI (P < .01). Our data indicate that 69% of diabetic and 27% of nondiabetic patients have HOMA-IR greater than 1.6, implying reduced insulin sensitivity in HD patients. The present results provide evidence that angiotensin inhibition improves insulin resistance, possibly preventing vascular injury in HD patients. Finally, our findings suggest that insulin resistance is prognostic of cardiovascular events in HD patients.     

Efficacy of erythropoietin on dialysis in patients with beta thalassemia minor

BACKGROUND: It is unknown whether chronic erythropoietin (EPO) treatment is able to normalize hemoglobin (Hb) levels and ameliorate cardiac remodeling avoiding blood transfusions in uremic blood transfusion-dependent patients with beta-thalassemia minor (beta-thal). METHODS: In 12 hemodialysis (HD) patients with beta-thal, requiring blood transfusions despite EPO therapy, we planned to increase Hb levels up to the target levels (11-12 g/dl) within a one-year period by administering progressively higher doses of EPO (correction phase). We also planned to maintain the Hb target for an additional year (maintenance phase). RESULTS: In the year before the study, patients required 3.3 +/- 0.9 units of packed red blood cells. At baseline, the Hb level obtained with an EPO dose of 212 +/- 73 U/kg/week i.v. was 8.2 +/- 0.8 g/dl. The EPO dose was gradually increased within the first year up to 458 +/- 78 U/kg/week at month 12 (correction phase) and then significantly tapered down during the maintenance phase (390 +/- 54 U/kg/week at month 24). During the correction phase, the Hb levels markedly increased (11.1 +/- 0.3 g/dl at month 12) and did not change in the maintenance phase. No blood transfusion was required throughout the 2 years of follow-up. Left ventricular (LV) mass index progressively decreased from the basal value of 144 +/- 12 to 124 +/- 11 g/m2 in the first year and normalized in all patients at month 24 (109 +/- 12 g/m2, p < 0.001); this occurred in the absence of any change of LV cavity volume index (<90 ml/m2). CONCLUSIONS: In HD transfusion-dependent patients with beta-thal, the administration of high EPO dose for 2 years permits the attainment and the maintenance of Hb targets without blood transfusions. This therapeutic approach permits a complete remission of concentric LV hypertrophy without any adverse effects on the vascular system.     

Adipocyte insulin binding and insulin action in chronic renal failure before and during continuous ambulatory peritoneal dialysis

In order to investigate the cellular mechanisms of the insulin resistance displayed by subjects with chronic renal failure, adipocyte insulin receptor status and in vitro insulin sensitivity were studied. Adipocytes from uremic subjects displayed normal maximum specific insulin binding (2.55 +/- 0.23 v 2.57 +/- 0.09% per 10 cm2 cell membrane, although half-maximum binding was observed at 91 +/- 8 (uremic) and 139 +/- 11 (control) pmol/L (P less than 0.005). In six subjects restudied after three months of continuous ambulatory peritoneal dialysis, maximum specific insulin binding fell as a consequence of changes in both receptor affinity and number (2.87 +/- 0.20 v 2.05 +/- 0.17% per 10 cm2 cell membrane, P less than 0.01). Basal and maximal rates of lipogenesis were similar in the uremic and control groups, and half-maximal stimulation occurred at 13.5 +/- 4.4 and 21.4 +/- 3.0 pmol/L, respectively (NS). During continuous ambulatory peritoneal dialysis, adipocyte insulin sensitivity did not change significantly as assessed by stimulation of lipogenesis or glucose uptake (half-maximal stimulation at 12.0 +/- 4.0 v 26.4 +/- 11.0 and 23.1 +/- 7.1 v 29.0 +/- 7.5 pmol/L, before and during dialysis, respectively). These data suggest either that adipose tissue and muscle display differential insulin sensitivities in chronic renal failure or that other factors such as circulating inhibitors of insulin action are not detected by in vitro assays.     

Role of anemia in the pathogenesis of left ventricular hypertrophy in end-stage renal disease

Left ventricular (LV) hypertrophy is common in end-stage renal disease, yet the factors associated with its development are poorly understood. LV mass index was determined by echocardiography in 78 patients who had been treated by dialysis for at least 3 months. A significant relation was evident between anemia and LV hypertrophy. The mean LV mass index was 158 +/- 6 g/m2 (mean +/- standard error) in patients in the lowest quartile of serum hemoglobin and 140 +/- 10, 132 +/- 7 and 120 +/- 8 g/m2 in the second, third and uppermost quartiles, respectively (p = 0.005). This relation persisted after adjusting for systolic blood pressure, treatment mode and suspected coronary artery disease. Forty-eight patients had paired studies. In these, LV mass index increased as hemoglobin decreased (coefficient = -0.81 g/m2/g/liter, p less than 0.025). These data indicate that anemia contributes to the development of LV hypertrophy in patients with end-stage renal disease.     

Effect of the renin-angiotensin system on limb circulation and metabolism during exercise in patients with heart failure

The maximal aerobic exercise capacity of patients with chronic heart failure is frequently decreased because of inadequate blood flow to working skeletal muscle. To investigate whether this reduced flow is in part due to interference by angiotensin II with arteriolar dilation in working muscle, the effect of the angiotensin-converting enzyme inhibitor captopril on leg blood flow, leg vascular resistance, leg oxygen consumption (VO2) and leg lactate release during maximal upright bicycle exercise was examined in 12 patients with heart failure (maximal VO2 10.7 +/- 3.1 ml/min per kg). Captopril decreased leg resistance at rest (258 +/- 115 to 173 +/- 67 U, p less than 0.01) and maximal exercise (68 +/- 69 to 45 +/- 29 U, p less than 0.01) associated with proportionately similar decreases in systemic vascular resistance. However, maximal exercise duration and maximal VO2 were unchanged and, at identical peak exercise work times, there was no improvement in leg blood flow (2.0 +/- 0.9 to 2.0 +/- 1.1 liters/min, p = NS), leg VO2 (261 +/- 104 to 281 +/- 157 ml/min, p = NS) or leg lactate release (269 +/- 149 to 227 +/- 151 mg/min, p = NS). These data suggest that, during exercise in patients with heart failure, angiotensin II does not interfere with blood flow to working skeletal muscle.