Treatment of renal anemia with darbepoetin alfa: results of an Austrian multicenter study

Darbepoetin alfa is a unique erythropoetic protein whose half-life is 3 times longer than that of recombinant human erythropoetin (rHuEPO). It corrects and maintains haemoglobin (Hb) concentrations at increased dosing intervals as compared to rHuEPO. The aim of this study was to evaluate the efficacy and safety of darbepoetin alfa administered as fixed unit doses. Haemodialysis patients (n = 250) maintained on stable rHuEPO treatment 2-3 times weekly (n = 200) were switched to darbepoetin alfa once weekly (QW). Treatment for patients on rHuEPO QW (n = 50) was changed to darbepoetin alfa every other week (Q2W). The route of administration (i.v. or s.c.) was kept unchanged. The dose of darbepoetin alfa was titrated to maintain Hb levels at 10-13 g/dL between baseline and the evaluation period (weeks 21-24; primary endpoint). There was no clinically relevant change in mean Hb levels between baseline (11.69 g/dL) and evaluation (-0.28 g/dL (95% CI: -0.43; -0.13)). Mean weekly dose requirements of darbepoetin alfa decreased by 13.3% from 36.7 micrograms (95% CI: 33.9; 39.7) to 31.8 micrograms (95% CI: 28.7; 35.2). This decrease was more pronounced in patients receiving darbepoetin alfa i.v. (-18.4%) as compared to those receiving it s.c. (-6.4%). Darbepoetin alfa was well tolerated. Overall safety data were consistent with those observed in other studies. These data confirm that unit dosing with darbepoetin alfa at increased dosing intervals and reduced dose effectively and safely maintains Hb levels in haemodialysis patients.     

Unit dosing of darbepoetin alfa for thetreatment of anemia in patients with end-stage renal disease being switched from recombinant human erythropoietin: Results of a phase IIIb, 27-week, multicenter, open-label study in Greek patients

Background:

Darbepoetin alfa is an erythropoietis-stimulating glycoprotein with a ∼3-fold longer t1/2 and greater biological activity compared with recombinant human erythropoietin (rHuEPO).

Objective:

The objective of this study was to evaluate the efficacy andtolerability of long-term (24-week) darbepoetin alfa treatment in maintaining hemoglobin (Hb) concentrations in the target range of 10 to 13 g/dL in patients undergoing dialysis; the patients were switched from rHuEPO to a less-frequent dosing regimen of darbepoetin alfa without an increase in dose.

Methods:

In this Phase IIlb, open-label, multicenter study, patients withend-stage renal disease (ESRD) undergoing dialysis who were receiving rHuEPO BIW or TIW at baseline were switched to darbepoetin alfa QW; patients receiving rHuEPO QW were switched to darbepoetin alfa Q2W Administration of darbepoetin alfa was by the same route as previous rHuEPO administration (IV or SC). Patients received darbepoetin alfa for 24 weeks, including a 20-week drug titration period followed by a 4-week, stable-dose evaluation period. The mode, dose, and frequency of administration of darbepoetin alfa were compared with those of baseline rHuEPO. Tolerability assessment was based on spontaneous reporting and laboratory tests (hematology, vital sign measurement, iron status, and biochemistry).

Results:

The study comprised 173 patients who were divided into 2 groups by route of administration (IV group, n = 146; SC group, n = 27). Mean (SE) adjusted increases in Hb concentration from baseline to the evaluation period for patients receiving darbepoetin alfa QW were 0.94 (0.32) g/dL and 0.38 (0.30) g/dL for the IV or SC routes, respectively (P = 0.004 and NS, respectively). For patients receiving darbepoetin alfa Q2W the mean (SE) adjusted increases in Hb concentration were 0.08 (0.53) g/dL and 0.48 (0.35) g/dL for the IV and SC routes, respectively (both, P = NS). No significant differences in IV/SC dose ratio were observed between the 2 routes of administration. In addition, no increases in darbepoetin alfa dose were observed. The most commonly reported adverse events were hypertension (8 patients [5%]) and vascular access thrombosis (4 [2%]). The incidence of treatment-related adverse events was 6 (3%).

Conclusions:

Darbepoetin alfa effectively maintained Hb concentrations within the target range without an increase in dose, even at a reduced dosing frequency. Overall, darbepoetin alfa was well tolerated.     

Darbepoetin alfa: a new therapy for the management of anaemia associated with chronic kidney disease

Darbepoetin alfa (Aranesp^®, Amgen, Inc., Thousand Oaks, California) is a new erythropoietic protein that corrects anaemia associated with chronic kidney disease (CKD) in the majority of patients. Darbepoetin alfa contains five N-linked carbohydrate chains compared with three in recombinant human erythropoietin (rHuEPO). The two additional sialic acid-containing carbohydrate chains prolong the serum half-life of darbepoetin alfa, resulting in greater biological activity and a reduced dosing frequency compared with rHuEPO. Clinical studies in patients with CKD have demonstrated that darbepoetin alfa is effective in correcting anaemia in rHuEPO-naive patients and in patients who have been converted from rHuEPO therapy. Darbepoetin alfa provides long-term maintenance of haemoglobin levels when administered once weekly or once every other week, with the possibility of once-monthly dosing in some patients. Darbepoetin alfa is well tolerated and has a safety profile similar to that of rHuEPO. Owing to its half-life being three times longer than rHuEPO, darbepoetin alfa can be administered at an extended dosing interval, without compromising efficacy. Lessfrequent dosing has potential benefits for both patients with CKD and healthcare providers. These benefits include reduced visits to the clinic, fewer injections and a reduced demand on staff and treatment facilities.     

Darbepoetin alfa: a new therapy for the management of anaemia associated with chronic kidney disease

Darbepoetin alfa (Aranesp, Amgen, Inc., Thousand Oaks, California) is a new erythropoietic protein that corrects anaemia associated with chronic kidney disease (CKD) in the majority of patients. Darbepoetin alfa contains five N-linked carbohydrate chains compared with three in recombinant human erythropoietin (rHuEPO). The two additional sialic acid-containing carbohydrate chains prolong the serum half-life of darbepoetin alfa, resulting in greater biological activity and a reduced dosing frequency compared with rHuEPO. Clinical studies in patients with CKD have demonstrated that darbepoetin alfa is effective in correcting anaemia in rHuEPO-naive patients and in patients who have been converted from rHuEPO therapy. Darbepoetin alfa provides long-term maintenance of haemoglobin levels when administered once weekly or once every other week, with the possibility of once-monthly dosing in some patients. Darbepoetin alfa is well tolerated and has a safety profile similar to that of rHuEPO. Owing to its half-life being three times longer than rHuEPO, darbepoetin alfa can be administered at an extended dosing interval, without compromising efficacy. Lessfrequent dosing has potential benefits for both patients with CKD and healthcare providers. These benefits include reduced visits to the clinic, fewer injections and a reduced demand on staff and treatment facilities.     

Anemia Management Trends in Hospital-Based Dialysis Centers (HBDCs), 2010 to 2013

Background

Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients.

Objective

Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease–related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013.

Methods

Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing.

Results

From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels <10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%.

Conclusions

These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing.     

Darbepoetin alfa administration to achieve and maintain target hemoglobin levels for 1 year in patients with chronic kidney disease

OBJECTIVE: To assess the efficacy and safety of every-other-week darbepoetin alfa therapy in treating anemia and maintaining hemoglobin levels for 1 year in patients with chronic kidney disease (CKD) who were not undergoing dialysis and who had not previously received erythropolesis-stimulating proteins (ESPs). PATIENTS AND METHODS: This multicenter 52-week study (evaluation period, weeks 20-32), a subanalysis of the Simplify the Treatment of Anemia with Aranesp study, enrolled patients with CKD who were not receiving dialysis (creatinine clearance < or =70 mL/min or estimated glomerular filtration rate [GFR] < or =60 mL/min). Patients evaluated in this analysis were not receiving ESPs, had hemoglobin concentrations less than 11 g/dL, and had transferrin saturation of 20% or higher during screening. Patients Initiated every-other-week darbepoetin alfa therapy at 0.75 microg/kg, with the dose subsequently titrated to maintain hemoglobin levels not to exceed 12 g/dL. The first study participant was enrolled on February 4, 2002, and the last participant completed the study on March 31, 2004. RESULTS: The analysis included 911 patients (mean [SD] age, 66.4 [14.2] years; 54.3% female; 55.3% white). The least squares mean evaluation hemoglobin concentration was 11.54 g/dL (95% confidence interval, 11.47-11.61 g/dL), and the change from baseline was 1.6 g/dL (95% confidence interval, 1.5-1.7 g/dL). The mean (SD) every-other-week darbepoetin alfa dose during evaluation was 44.5 (33.7) microg. Iron supplementation was administered to 573 patients (62.9%) during the study. Darbepoetin alfa was well tolerated throughout the study period. CONCLUSION: Darbepoetin alfa initiated every other week safely and effectively treated anemia and maintained hemoglobin for 1 year in patients with CKD who were not undergoing dialysis and who were not receiving prior ESP therapy.     

Effect of erythropoietin in continuous ambulatory peritoneal dialysis patients: comparison between intravenous and intraperitoneal administration.

The administration of recombinant human erythropoietin (rHuEPO) in CAPD patients is usually done subcutaneously. Only a few authors have reported on its intraperitoneal (IP) administration. We compared the effect of IP administration of rHuEPO in CAPD patients to that of intravenous (IV) administration. Ten anemic CAPD patients injected rHuEPO into their dialysis bag once a day, 3 times a week, for 18 weeks. The initial dose was 12,000 U. The dwell time of the exchanges with rHuEPO was about 6 hours. Nine other anemic CAPD patients were treated with IV rHuEPO once a week for 18 weeks. The initial dose was 6000 U. In the IP group the hematocrit rose from 24.04 +/- 2.7% to 33.3 +/- 3.8% (mean +/- SD). In the IV group 2 patients were excluded from the efficiency evaluation. In 7 of the 9 patients in the IV group, the hematocrit rose from 23.27 +/- 2.6% to 32 +/- 5.5% (mean +/- SD). The intraperitoneal administration of rHuEPO in CAPD patients is sufficient in improving anemia, although it requires a much larger dosage to yield the same level of improvement as the one obtained with the intravenous administration. However, in patients on continuous cycling peritoneal dialysis or IP dialysis, a smaller dosage during the prolonged dwell time may be effective.     

Comparison of effects of darbepoetin alfa and epoetin alfa on serum endothelin level and blood pressure

It is well known that epoetin alfa increases serum endothelin (ET)-1 and blood pressure. No data are available, however, on the effects of darbepoetin alfa on serum ET-1 and blood pressure. This study was conducted to compare the effects of darbepoetin alfa and epoetin alfa on serum ET-1 and blood pressure in patients on hemodialysis (HD). A total of 42 patients on HD were included in the study. Serum samples for measuring levels of ET-1 were taken 30 min after administration of epoetin alfa. After blood samples had been taken from all patients, epoetin alfa was changed to darbepoetin alfa. Three months after the start of darbepoetin alfa treatment, blood samples were taken to measure the same parameters. Mean arterial blood pressure was measured before recombinant human erythropoietin (EPO) administration and 30 min after EPO administration while patients were taking epoetin alfa or darbepoetin alfa. Injection of epoetin alfa or darbepoetin alfa significantly increased serum ET-1 levels compared with levels in those patients who were not on EPO therapy (P < .05). When the effects of epoetin alfa on serum ET-1 level were compared with those of darbepoetin alfa, the 2 types of EPO were found to increase serum ET-1 levels similarly (P > .05). Administration of epoetin alfa or darbepoetin alfa increased systolic and diastolic blood pressures significantly over values in the control group (P < .05). Serum systolic and diastolic blood pressures increased similarly after injection of epoetin alfa or darbepoetin alfa. Administration of darbepoetin alfa increased blood pressure in patients on HD in a way that was positively correlated with enhanced ET-1 release; a similar correlation was noted with epoetin alfa.     

Pressure sore anemia: response to erythropoietin.

Anemia in patients with grade IV pressure sores is usually refractory to therapy with iron salts, and red cell transfusions are commonly required when reconstructive surgery is performed. The anemia is characterized by hypoferremia, reticulocytopenia, and normal-to-increased serum ferritin. Five patients with this anemia were treated with recombinant human erythropoietin (rHuEPO) in doses of 50 to 100 U/kg, given subcutaneously three times per week. The hemoglobin increased in every patient; the mean (+/- SD) value at the initiation of treatment was 8.8 +/- 1.0 g/dL, and after a median of 4 weeks of therapy, it was 12.4 +/- 1.6 g/dL (p less than .001). No adverse effects of treatment were observed. It is concluded that rHuEPO is a promising new agent for pressure sore anemia, but randomized, controlled clinical trials will be required to firmly establish its place in the management of patients with this type of anemia.     

Effect of human recombinant erythropoietin on anaemia and dialysis efficiency in patients undergoing continuous ambulatory peritoneal dialysis

The effect of long-term treatment with human recombinant erythropoietin (rHuEPO) has been studied in nine end-stage renal disease patients on continuous ambulatory peritoneal dialysis (CAPD). RHuEPO was administered subcutaneously twice weekly in rising doses starting with 50 Ukg-1 body weight. After 3 months of rHuEPO haemoglobin increased from 77.7 +/- 3.2 to 112.7 +/- 5.6 g l-1 (P less than 0.03), haematocrit rose from 22.8 +/- 1.2 to 30.3 +/- 1.7% (P less than 0.01). A consistent decrease in ferritin concentration was observed during this time (P less than 0.05). After 12 months of rHuEPO treatment and increased oral iron supplementation the rises of haemoglobin and haematocrit remained stable without other significant haematological changes. The rHuEPO-induced rise in haematocrit was associated with an increased peritoneal ultrafiltration (UF) without change in diuresis and body weight. UF improved from 128 +/- 28 ml 4 h-1 dwell time to 273 +/- 45 ml 4 h-1 (P less than 0.03) within 3 months of rHuEPO treatment, and remained stable during the following study period (month 12: 253 +/- 43 ml 4 h-1, P less than 0.05). The rise in UF resulted in improved peritoneal clearances of creatinine, urea, potassium, and phosphate (P less than 0.05, month 3). No change was observed in serum urea, creatinine, calcium, and potassium. Serum phosphate increased throughout the first 6 months of rHuEPO (P less than 0.05). No severe adverse effects of rHuEPO treatment could be observed. The present results demonstrate that long-term subcutaneous administration of rHuEPO is effective in correcting renal anaemia in CAPD patients and may improve dialysis efficiency by increased peritoneal ultrafiltration.     

Association between serum n-terminal pro-brain natriuretic peptide concentration and left ventricular dysfunction and extracellular water in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: This study investigated the association between serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels and extracellular water (ECW%) and left ventricular (LV) dysfunction in continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: The study involved 30 stable CAPD patients: 14 males, 16 females; mean age 52 +/- 14 years; mean CAPD duration 34 +/- 12 months; 12 with diabetes mellitus (DM) and 18 non-DM. Serum NT-pro-BNP levels were determined using electrochemiluminescence immunoassay. Baseline echocardiography was performed using a Hewlett-Packard Sonos 1000 (Andover, Massachusetts, USA) device equipped with a 2.25-MHz probe, allowing M-mode, two-dimensional, and pulsed Doppler measurements. Left ventricular mass index (LVMI) was calculated according to the Penn formula. A multifrequency bioimpedance analyzer was used; ECW% was calculated as a percentage of total body water and was considered the index of volume load. RESULTS: (1) Serum NT-pro-BNP level, ECW%, LVMI, and LV ejection fraction in CAPD patients were 3924 (240 - 74460) pg/mL, 36.7% +/- 2.2%, 158 +/- 48 g/m2, and 60.5% +/-11.2%, respectively. (2) Patients were divided into three tertiles (10 patients each) according to their serum NT-proBNP concentration [1st tertile 1168 (240 - 2096), 2nd tertile 4856 (2295 - 20088), 3rd tertile 35012 (20539 -74460) pg/mL]. The tertiles did not differ significantly in terms of age, sex, presence of DM, body mass index, or PD duration. Patients in the 3rd tertile (highest serum NT-proBNP concentration) had the highest LVMI (126 +/- 45 vs 160 +/-41 vs 200 +/- 23 g/m2 for 1st, 2nd, 3rd tertiles, respectively) and the lowest LV ejection fraction (66% +/- 11% vs 62% +/-6% vs 55% +/- 9%). ECW% did not differ significantly between tertiles (35.5% +/- 2.0% vs 37.5% +/- 2.0% vs 36.5% +/-2.0%). (3) In CAPD patients, serum NT-pro-BNP levels correlated positively with LVMI (r = 0.628, p = 0.003) and negatively with LV ejection fraction (r = -0.479, p = 0.033). Serum NT-pro-BNP levels did not correlate with ECW% (r = 0.227, p = 0.25). (4) Stepwise regression analysis showed that LV ejection fraction (beta = -0.610, p = 0.015) and LVMI (beta = 0.415, p = 0.007) were independently associated with the serum NT-pro-BNP concentration. CONCLUSIONS: There was no link between ECW% and serum NT-pro-BNP concentration. Thus, serum NT-pro-BNP levels may not provide objective information with respect to pure hydration status in CAPD patients. In contrast, serum NT-pro-BNP levels were linked to LVMI and LV ejection fraction in CAPD patients. Therefore, while the serum NT-proBNP concentration might not be a useful clinical marker for extracellular fluid volume load, it appears useful for evaluating LV hypertrophy and LV dysfunction in CAPD patients.     

Efficacy of recombinant human erythropoietin in critically ill patients admitted to a long-term acute care facility: a randomized, double-blind, placebo-controlled trial

CONTEXT: Anemia is common in the critically ill and results in a large number of red blood cell transfusions. Recent data have shown that red blood cell transfusions in critically ill patients can be decreased with recombinant human erythropoietin (rHuEPO) therapy during their intensive care unit stay. OBJECTIVE: To assess the efficacy of rHuEPO therapy in decreasing the occurrence of red blood cell transfusions in patients admitted to a long-term acute care facility (LTAC). DESIGN: A prospective, randomized, double-blind, placebo-controlled, multiple-center trial. SETTING: Two long-term acute care facilities. PATIENTS: A total of 86 patients who met eligibility criteria were enrolled in the study with 42 randomized to rHuEPO and 44 to placebo. INTERVENTIONS: Study drug (rHuEPO 40,000 units) or a placebo was administered by subcutaneous injection before day 7 of long-term acute care facility admission and continued weekly for up to 12 doses. MAIN OUTCOME MEASURES: The primary efficacy end point was cumulative red blood cell units transfused. Secondary efficacy end points were the percent of patients receiving any red blood cell transfusion; the percent of patients alive and transfusion independent; cumulative mortality; and change in hematologic variables from baseline. Logistic regression was used to adjust the odds ratio for red blood cell transfusion. All end points were assessed at both study day 42 and study day 84. RESULTS: The baseline hemoglobin level was higher in the rHuEPO group (9.9 +/- 1.15 g/dL vs. 9.3 +/- 1.41 g/dL, p = .02) as was the pretransfusion hemoglobin level (8.0 +/- 0.5 g/dL vs. 7.5 +/- 0.8 g/dL, p = .04). At day 84, patients receiving rHuEPO received fewer red blood cell transfusions (median units per patient 0 vs. 2, p = .05), and the ratio of red blood cell transfusion rates per day alive was 0.61 with 95% confidence interval of 0.2, 1.01, indicating a 39% relative reduction in transfusion burden for the rHuEPO group compared with placebo. There was also a trend at day 84 toward a reduction in the total units of red blood cells transfused in the rHuEPO group (113 units of placebo vs. 73 units of rHuEPO). Patients receiving rHuEPO were also less likely to be transfused (64% placebo vs. 41% rHuEPO, p = .05; adjusted odds ratio 0.47, 95% confidence interval 0.19, 1.16). Most of the transfusion benefit of rHuEPO occurred by study day 42. Increase in hemoglobin from baseline to final was greater in the rHuEPO group (1.0 +/- 2 g/dL vs. 0.4 +/- 1.7 g/dL, p < .001). Mortality rate (19% rHuEPO, 29.5% placebo, p = .17; relative risk, 0.55, 95% confidence interval 0.21-1.43) and serious adverse clinical events (38 % rHuEPO, 32% placebo, p = .65) were not significantly different between the two groups. CONCLUSIONS: In patients admitted to a long-term acute care facility, administration of weekly rHuEPO results in a significant reduction in exposure to allogeneic red blood cell transfusion during the initial 42 days of rHuEPO therapy, with little additional benefit achieved with therapy to 84 days. Despite receiving fewer red blood cell transfusions, patients treated with rHuEPO achieve a higher hemoglobin level.     

Effect of darbepoetin alfa administered once monthly on maintaining hemoglobin levels in older patients with chronic kidney disease

Background: The anemia of chronic kidney disease (CKD) is associated with increased hospitalizations, increased cardiovascular morbidity and mortality, and diminished quality of life in the elderly. Darbepoetin alfa is an erythropoiesis-stimulating agent that has been shown to be effective in treating anemia in patients with CKD (but not on dialysis) when administered using extended-dosing regimens.Objective: The purpose of this post hoc analysis was to examine the efficacy and safety profile of once-monthly (QM) darbepoetin alfa in study patients stratified according to age (ie, <65, 65–74, and ≥75 years).Methods: Patients with CKD but not on dialysis, receiving darbepoetin alfa every other week (Q2W), and with stable hemoglobin (Hb) levels between 11 and 13 g/dL, inclusive, were enrolled in this 33-week, multicenter, open-label, single-arm study. The study was carried out at 36 US centers and consisted of a 24-week QM darbepoetin alfa dose-titration period followed by an 8-week evaluation period. Hb levels were measured Q2W. Study results were stratified according to patient age (<65, 65–74, and ≥75 years).Results: A total of 152 patients (79 women, 73 men) were enrolled; 55 patients (36%) were <65 years of age, 46 (30%) were 65 to 74 years of age, and 51 (34%) were ≥75 years of age. In patients who received ≥1 dose of darbepoetin alfa, Hb levels ≥11 g/dL were maintained in 76%, 80%, and 71% of patients aged <65, 65 to 74, and ≥75 years, respectively. For patients who completed the study, the proportions who maintained Hb levels ≥11 g/dL were 83%, 88%, and 85%, respectively, for the 3 age groups. The safety profile of QM darbepoetin alfa in this study was consistent with that expected in patients with CKD not receiving dialysis.Conclusions: Darbepoetin alfa administered QM maintained Hb levels ≥11 g/dL in patients with CKD (not on dialysis) aged <65, 65 to 74, and ≥75 years. This treatment regimen may help optimize anemia management for older community-dwelling and long-term care patients.     

Randomized, open label, controlled clinical trial of oral administration of an egg albumin-based protein supplement to patients on continuous ambulatory peritoneal dialysis.

BACKGROUND/AIM: Malnutrition is highly prevalent in patients on continuous ambulatory peritoneal dialysis (CAPD) and is a strong predictor of increased morbidity and mortality. Therefore, the aim of this study was to evaluate the effect of oral administration of an egg albumin-based protein supplement on the nutritional status of CAPD patients. METHODS: In this randomized, open label, controlled clinical trial, 28 CAPD patients were allocated to a study (n = 13) or a control (n = 15) group. Both groups received conventional nutritional counseling; the study group received, additionally, an oral egg albumin-based supplement. During a 6-month follow-up, all patients had monthly clinical and biochemical evaluations and quarterly assessments of adequacy of dialysis and nutrition. RESULTS: Serum albumin Levels were not different between groups; however, a significant increase (baseline vs final) was observed in the study group (2.64+/-0.35 vs 3.05+/-0.72 g/dL) but not in the control group (2.66+/-0.56 vs 2.80+/-0.54 mg/dL). Calorie and protein intake increased more in the study group (calories 1331+/-432 vs 1872+/-698 kcal; proteins 1.0+/-0.3 vs 1.7+/-0.7 g/kg) than in the control group (calories 1423+/-410 vs 1567+/-381 kcal; proteins 1.0+/-0.4 vs 1.0+/-0.3 g/kg). Similarly, non-protein nitrogen appearance rate (nPNA) increased significantly more in the study (1.00+/-0.23 vs 1.18+/-0.35 g/kg/day) than in the control group (0.91+/-0.11 vs 0.97+/-0.14 g/kg/ day). Triceps skinfold thickness (TSF) and midarm muscle area (MAMA) displayed a nonsignificant trend to a greater increase in the study group (TSF 16.7+/-8.7 vs 18.3+/-10.7 mm; MAMA 23.8+/-6.2 vs 25.8+/-5.9 cm2) than in controls (TSF 16.4+/-5.7 vs 16.9+/-7.0 mm; MAMA 28.7+/-7.8 vs 30.0+/-7.9 cm2). At the end of follow-up, the frequency of patients with moderate or severe malnutrition decreased 6% in the control group and decreased 28% in the study group. At the final evaluation, the most important predictors of serum albumin were the oral egg albumin-based supplement administration and protein intake (p < 0.05); secondary predictors (p = 0.06) were peritoneal transport rate and MAMA. CONCLUSIONS: In the study group, oral administration of the egg albumin-based supplement significantly improved serum albumin, calorie and protein intake, and nPNA, and, compared to controls, this maneuver was associated with a trend to increased anthropometric parameters and improved Subjective Global Assessment evaluation. Oral administration of the albumin supplement and protein intake were the most significant predictors of serum albumin at the end of follow-up. This oral supplement may be a safe, effective, and cheap method to improve nutritional status in peritoneal dialysis patients.     

Association of in vitro oxidative stress, serum ferritin concentration and C-reactive protein in febrile emergency room patients

BACKGROUND: Both C-reactive protein (CRP) and ferritin have been reported to reflect the extent of oxidative stress and inflammation in individual patients and may be useful markers of disease activity and mortality risk. Exposure to oxidative stress has been reported to increase ferritin synthesis. We investigated the relationship between oxidative stress with CRP and ferritin concentrations in febrile emergency room patients to test the hypothesis whether the intensity of oxidative stress correlated with serum ferritin concentration. METHODS: Six normal healthy volunteers and 59 emergency room, febrile patients with body temperature >38.3 we enrolled before receiving medical treatment. Baseline measurements included complete blood count, blood biochemistry, CRP and serum ferritin concentrations, and transferring saturation (TSAT). The intensity of lucigenin-enhanced chemiluminescence (LucCL), corresponding to the level of superoxide, was detected by luminometer. RESULTS: In febrile patients, plasma LucCL intensity was higher than in normal healthy volunteers (P<0.05). The group with bacterial infection had higher serum ferritin (319.4+/-53.7 vs 102.0+/-21.2 ng/dL, P<0.05) and CRP concentrations (7.2+/-1.2 vs 2.2+/-0.6 mg/dL; P<0.05) than the group without bacterial infection. There were no differences in leukocytes (9790+/-606 vs 9577+/-656 /mm3) or plasma LucCL intensity (423.7+/-10.8 vs 409.5+/-6.9 relative light unit?RLU?;) between the two groups. LucCL intensity showed no correlation with serum ferritin concentration (r= -0.0599, P>0.05), TSAT(r= -0.0592, P>0.05), CRP(r= 0.1027, P>0.05) and absolute neutrophil counts (r= 0.1059; P >0.05). CONCLUSION: In this sample of emergency room febrile patients, plasma LucCL intensity was higher than in normal healthy control volunteers. A single point measurement of oxidative stress, particularly plasma LucCL intensity, may not be sufficient to differentiate the origin of fever in febrile patients. These data demonstrate that patients with bacterial infection had increased levels of CRP and ferritin, but this was not associated with LucCL intensity.     

The effect of hemoglobin concentration on peritoneal mass transfer and drain volumes in continuous ambulatory peritoneal dialysis.

OBJECTIVE: To determine whether a correlation exists between hemoglobin levels and peritoneal mass transfer or drain volumes in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Prospective study of two groups of CAPD patients, identified on the basis of their stable hemoglobin levels. Group A--hemoglobin less than 8.5 g/dL; Group B--hemoglobin greater than 10.5 g/dL. Peritoneal mass transfer and drain volumes were measured for each patient, after which a subgroup of Group A was treated with rHuEPO (forming Group C) and measurements repeated once hemoglobin had risen by at least 2.0 g/dL. SETTING: Single renal unit of a university teaching hospital. PATIENTS: Twenty-seven patients established on CAPD, selected according to their stable hemoglobin level. Group A--14 patients; Group B--13 patients; Group C (subgroup of A)--8 patients. MAIN OUTCOME MEASURES: Difference between peritoneal mass transfer or drain volume in Group A versus Group B, and in Group C before and after rHuEPO therapy. Serum biochemical parameters in Group C before and after rHuEPO therapy. RESULTS: No statistically significant differences in any of the parameters measured were found between groups A and B, or before and after rHuEPO therapy in Group C. CONCLUSIONS: Peritoneal transfer of small solutes and water is not influenced by hemoglobin level, and does not change following otherwise effective treatment with rHuEPO.     

A multicenter retrospective cohort study of practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia

BACKGROUND: Darbepoetin alfa is the second erythropoietic protein to be approved for the treatment of chemotherapy-induced anemia (CIA). In the clinical setting, darbepoetin alfa can be administered less frequently than epoetin alfa with similar efficacy. Practice patterns and outcomes associated with the use of darbepoetin alfa and epoetin alfa in the clinical setting have not been reported. OBJECTIVE: This study compared practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for CIA at oncology practices in the United States. METHODS: This was a multicenter retrospective cohort study. Data were abstracted from the medical charts of consecutive patients who began darbepoetin alfa treatment between August 1 and October 4, 2002, or epoetin alfa treatment between April 1 and July 31, 2002, and were receiving concurrent chemotherapy. These data were used to determine the initial dose and dosing schedule, dose changes, and changes in hemoglobin concentrations after 4, 8, and 12 weeks of treatment, adjusted for red blood cell (RBC) transfusions, and the incidence of RBC transfusions over time. To minimize potential bias, the study protocol defined specific end points and prespecified analytic techniques for assessing clinical outcomes with the 2 agents. RESULTS: The records of 1391 patients from 16 community and hospital outpatient oncology clinics were abstracted. Of these, 1293 patients (93.0%) received only 1 erythropoietic agent (darbepoetin alfa, 735 [56.8%]; epoetin alfa, 558 [43.2%]); the remainder received both agents. In the patients who received darbepoetin alfa, most (553 [75.2%]) received an initial dosage of 200 microg q2wk. A similar proportion (414 [74.2%]) received epoetin alfa at an initial dosage of 40,000 U qwk. As these were the regimens for the majority of patients whose records were abstracted, the results reported here are for these patients. The dose was increased in 63 darbepoetin alfa recipients (11.4%) and 58 epoetin alfa recipients (14.0%) at a median of 7 weeks. After 12 weeks, the 2 groups had an identical mean imputed change from baseline in hemoglobin concentration (1.0 g/dL), and the incidence of RBC transfusions during treatment was also similar between groups (darbepoetin alfa, 44553 [8.0%]; epoetin alfa, 39414 [9.4%]). CONCLUSIONS: Darbepoetin alfa 200 microg q2wk was used as a standard regimen for CIA at the 16 US oncology practices participating in this study. It appeared to be as effective as epoetin alfa 40,000 U qwk, with a reduced frequency of dosing.     

Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis

OBJECTIVE: The aim of this multicenter, randomized, open-label study was to compare the pharmacokinetic and pharmacodynamic profiles of darbepoetin alfa, a new erythropoiesis-stimulating protein, and recombinant human erythropoietin (epoetin) after repeated intravenous dosing in patients with chronic kidney disease receiving hemodialysis. METHODS: Forty-seven patients were randomized to receive darbepoetin alfa administered once weekly (n = 17) or 3 times weekly (n = 15) or epoetin administered 3 times weekly (n = 15) for up to 52 weeks. Pharmacokinetic profiles were measured during weeks 1 and 12 and at hemoglobin steady state (defined as a hemoglobin concentration within the target range for 4 consecutive weeks after week 12 with no change in study drug dose) or between weeks 36 and 40, whichever occurred first. RESULTS: At each of the 3 time points evaluated, the terminal half-life of darbepoetin alfa was 2 to 3 times longer and the clearance approximately 4 times slower than those of epoetin. At week 12, the terminal half-life was 23.4 hours with darbepoetin alfa once weekly, 18.3 hours with darbepoetin alfa 3 times weekly, and 8.0 hours with epoetin 3 times weekly. The pharmacokinetics of darbepoetin alfa was not dependent on dose or time. Mean hemoglobin values at steady state were all approximately 11 g/dL, within the target range of 9.0 to 13.0 g/dL. Safety analyses revealed no differences between darbepoetin alfa and epoetin. CONCLUSIONS: The pharmacokinetic and pharmacodynamic profiles and safety data for darbepoetin alfa demonstrate that it can be administered less frequently than epoetin in patients with chronic kidney disease receiving hemodialysis, thus simplifying anemia management.     

QT dispersion and signal-averaged electrocardiogram in hemodialysis and CAPD patients.

OBJECTIVE: The aim of this study was to compare QT dispersion (QTd) and signal-averaged electrocardiogram (SA-ECG) parameters that may predict risk of malignant arrhythmias in patients on hemodialysis (HD), on continuous ambulatory peritoneal dialysis (CAPD), and in controls. SETTING: Controlled cross-sectional study in a tertiary-care setting. PATIENTS: 28 HD (M/F 18/10; mean age 32 +/- 9 years), 29 CAPD (M/F 17/12; mean age 34 +/- 10 years), and 29 healthy controls (M/F 17/12; mean age 32 +/- 8 years) were included. INTERVENTIONS: On ECG, minimum (QTmin) and maximum (QTmax) QT duration and their difference (QTd) were measured. In SA-ECG, duration of filtered QRS, HFLA signals less than 40 microV, and RMS voltage (40 ms) were also measured. RESULTS: Higher serum Ca2+ and lower K+ levels were found in CAPD compared to HD. All QT parameters were increased in HD and CAPD compared to controls. QT dispersion was significantly prolonged in HD compared to CAPD. In HD, QTd was correlated with left ventricular (LV) mass index (r = 0.53, p = 0.004), but not in CAPD (r = -0.09, p = 0.63). QT dispersion was significantly prolonged in patients with LV hypertrophy compared to patients without hypertrophy on HD (68 +/- 18 ms vs 49 +/- 18 ms, p = 0.008). In the analysis of SA-ECG, 3 of the 28 (11%) HD and 2 of the 29 (7%) CAPD patients had abnormal late potentials. Patients on HD and CAPD had significantly higher filtered-QRS duration compared to controls (105 +/- 15 ms and 104 +/- 12 ms vs 95 +/- 5 ms, respectively, p = 0.04). Patients with LV hypertrophy had higher filtered-QRS duration compared to patients without hypertrophy (109 +/- 12 ms vs 95 +/- 8 ms, p < 0.001). CONCLUSION: Dialysis patients had prolonged QTd and increased filtered-QRS duration in SA-ECG compared to controls. Patients on HD had longer QTd than patients on CAPD. QTd has been correlated to LV mass index in HD, but not in CAPD. This difference might be due to the effect of different dialysis modalities on electrolytes, especially the higher serum Ca2+ levels.     

Association of anion gap with thyroid dysfunction and nodular goiter in CAPD patients.

OBJECTIVE: To investigate the association of clinical parameters and serum anion gap with thyroid dysfunction and nodular goiter in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Cross-sectional study. SETTING: Single dialysis unit and outpatient clinic. PATIENTS: This study Included 89 uremic patients on CAPD. Gender ratio was 50 males to 39 females (M/F = 1.28); mean age was 54.8 years. MAIN OUTCOME MEASURES: We investigated the prevalence of nodular goiter and thyroid dysfunction with a 10-MHz high-frequency ultrasound scanner and immunoassay kits. RESULTS: Nodular goiter was detected in 52.8% (47/89) of the CAPD patients. Patients with nodular goiter were older than those without goiter (57.7 vs 51.5 years, p < 0.05). Nodular goiter was found more frequently in females than in males (66.7% vs 44.0%, p < 0.05). Patients with nodular goiter had longer duration of CAPD than patients without goiter (51.6 +/- 42.9 vs 31.0 +/- 28.1 months, p < 0.02). In addition, CAPD patients with goiter had a higher serum anion gap (AG) (16.8 +/- 3.3 vs 14.0 +/- 4.5 mEq/L, p < 0.02) and a lower weekly creatinine clearance (55.9 +/- 12.6 vs 64.6 +/- 21.1 L/week/1.73 m2, p < 0.05) than patients without goiter. As serum AG gradually Increased, significant alteration of thyroid parameters developed In the following sequence: (1) reduction of total T3 level at an AG level of 15, (2) elevation of thyrotropin (TSH) and Increased prevalence of goiter at an AG of 18, and (3) reduction of free T4 and total T4 levels and elevation of TSH, with further increased frequency of goiter at an AG of 20 mEq/L. CONCLUSION: According to this study, age, gender, dialysis duration, serum AG, and weekly creatinine clearance are correlated with prevalence of goiter in CAPD patients. Sequential alteration of thyroid function and Increasing frequency of nodular goiter correlated with higher serum AG. There are two explanations for this correlation: the level of serum AG may be an indirect index of the level of serum goitrogens, and higher serum AG and Increased frequency of nodular goiters might be a reflection of loss of residual renal function. Therefore, thyroid function screening and goiter detection using ultrasound should be considered when examining CAPD patients with progressively elevating serum anion gap.