Darbepoetin Alpha Research Articles

Response of patients with sickle cell anaemia and end-stage renal disease to erythropoietin treatment

Sir, Generally, end-stage renal disease (ESRD) due to sickle cell anaemia (SCA) occurs in <1% of patients receiving renal replacement treatment. For this reason, data about this patient group are very limited and controversial. Both the unresponsiveness of erythropoietin (Epo) treatments and their positive effects for extending the blood transfusion intervals of such patients were previously reported in studies with only one to three patients [1–3]. In this study, the responses of eight patients with concurrent SCA and ESRD to Epo treatment were retrospectively investigated. A total of eight patients (four males, four females; mean age, 42 ± 11.7 years) with ESRD and SCA who were followed up between May 2001 and October 2009 were studied, including one pre-dialysis (Stage 4–5), two peritoneal dialysis and five haemodialysis patients. During the study period, one patient died and one patient was transferred to another centre after renal transplantation. The data of the patients were obtained from the patient records and routine monthly dialysis recordings. Unscheduled haemoglobin measurements recorded in the emergency room during painful episodes and control haemoglobin levels measured after transfusions were recorded but not included in the calculations. The means of the haemoglobin and ferritin levels, transferrin saturation indices, blood transfusion requirements and hospitalizations were recorded before and after Epo treatment over a period of 12 months. The results of pre- and post-Epo treatment were compared using the paired t-test. In four haemodialysis patients, treatment with epoetin beta had been started after blood transfusions when haemoglobin levels rose to approximately 7–8 g/dL, with a dosage of 75 U/kg/week. Despite this therapy, haemoglobin concentrations fell to 5–5.5 g/dL in 2 months. Therefore, the epoetin beta dosage was increased to and maintained at 150 U/kg/week. The other four patients were both started and maintained on Epo therapy at the upper end of the dosage range allowed for ESRD patients, according to guidelines. Haemoglobin levels of all the patients were recorded throughout the study period while they were under the maximum maintenance Epo dosage with the following results: 0.75 μg/kg/week s.c. for darbepoetin alpha (one pre-dialysis and two peritoneal dialysis patients) and 150 U/kg/week s.c. for epoetin beta (five haemodialysis patients). No patient was receiving iron therapy and only one patient received the hydroxyurea treatment with an adjusted ESRD dose (500 mg/day) during the study period. There was no significant difference between the means of the haemoglobin (5.6 ± 0.4 vs 5.5 ± 0.4 g/dL) and ferritin levels (>2000 vs >2000 ng/mL), transferrin saturation indices (72.6 ± 19.5 vs 76.5 ± 21.2%), numbers of hospitalizations (5.5 times per year—min. 3, max. 8 vs 6.0 times per year—min. 2, max. 9) and blood transfusion needs and rates (minimum 1–2 U/2–3 months, maximum 1–3 U/1–2 months) before and after Epo treatment. The haemoglobin levels of the patients still decreased to between 4.0 and 4.5 g/dL once or twice during the year Epo was being administered (Table 1). There was no newly developed thromboembolic event in any of the patients during Epo treatment. Table 1 Characteristics of SCA and ESRD patients and summary of Epo response Epo treatment was continued (14 ± 2.2 months) in one pre-dialysis and two peritoneal dialysis patients and was ceased in five patients due to unresponsiveness to treatment. In one of the patients in whom Epo treatment was ceased, the treatment had been administered from May 2001 to September 2006, ceased in 2006 and the patient died in 2008. The mean time of Epo treatment in the other four patients in whom Epo had been stopped due to unresponsiveness was 18 ± 6.3 months. In this retrospective study, the unresponsiveness of Epo treatment, resulting in target haemoglobin levels not being reached in patients with concurrent SCA and ESRD, could possibly be due to the fact that the precise cause of anaemia in this patient group is not Epo insufficiency. On the other hand, since basal endogenous Epo levels in SCA patients are shown to be higher than in the normal population, the Epo requirement may also be much higher than for other ESRD patients following the development of renal failure [4]. With regard to the variable individual response to Epo treatment, until more precise data are available, with a higher number of patients with SCA and ESRD from different centres, it would be appropriate to attempt treatment with the maximum possible dose for a period and then to stop this expensive treatment if the expected response cannot be achieved. Conflict of interest statement. None declared.

Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: Possible role of phospho-70-ribosomal-S6 kinase

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that occurs in some patients with renal insufficiency. Exposure to gadolinium-based contrast agents (GdCA) has been associated with the development of NSF. No uniformly effective treatment options exist. We present immunohistochemical evidence to show that the proliferating fibrocytes of NSF express phospho-70-s6 kinase (PI-3-K), a protein downstream of PI-3-K, and the target of the drug rapamycin. In our patient, use of rapamycin resulted in rapid clinical improvement marked by reduced edema, reduced skin induration, and decreased pain. This suggests a possible role for PI-3-K and rapamycin (mTOR) pathways in the pathogenesis of NSF. Drugs that inhibit these pathways may be a target for future therapy. While our patient did attribute disease onset to GdCA exposure, used on a single occasion for abdominal imaging, he was also exposed to iron, calcium, and darbepoetin alpha at the time of imaging.

Monthly Administration of Darbepoetin Alpha in Saudi Hemodialysis Patients: is it a Practical Regimen?

Aim : In this study, we investigated the efficacy and safety of conversion stable hemodialysis patients from the current short-acting r-HuEPO (EPO beta) to the long-acting darbepoetin. Method : The study included 12 months of darbepoetin administration. The mean initial conversion ratio was 350 IU of short acting r-HuEPO to 1 microgram of darbepoetin. We adjusted the dose of darbepoetin to maintain hemoglobin levels between 11-12 g/dL. The study was carried out on 2 consecutive phases of 12 weeks each. Success with the extended dosing interval was defined as maintenance of mean hemoglobin> 10.0 g/dl during each phase.Result : There were 26 patients who fulfilled the entry criteria. Their mean age was 47.0 ± 17.13 years, and the mean duration on hemodialysis was 55.8 ± 14.0 months. The mean weekly dose increased from 28.75 ± 4.2 μg in the biweekly frequency of dosing to 38.5±3.9 μg after switching to the monthly protocol. The hemoglobin levels were maintained at therapeutic range without statistically significant change throughout the study; the mean hemoglobin levels was 10.81± .86 g/L at start of the study and 10.86 ± .76 g/L at the end of 6 months. Continuing the darbepoetin in 12 patients for one year disclosed no significant change of the conversion ratio of the drug, and the mean hemoglobin levels remained within the targeted limits.Conclusion: Darbepoetin alpha is effective and safe for the treatment anemia in hemodialysis patients even at monthly dose intervals and for long-term. With the the above mentioned conversion ratio and current prices, darbepoetin seems more expensive than the short acting erythropoetin beta by 15%, 58 % for the biweekly and monthly doses respectively. However, the longer dosing intervals are certainly much better convenience to patients and care takers in comparison with the currently used short acting ESAs.

Evolución del índice de resistencia a darbepoetina alfa en pacientes dializados que cambian de administración semanal a quincenal en la práctica clínica

Darbepoetin alpha (DA) administered every-other-week (Q2W) is efficacious and safe for the treatment of anaemia in patients undergoing dialysis. There are no data available regarding the evolution of erythropoietic resistance index (ERI) after conversion from weekly (QW) to Q2W administration of DA in clinical practice. Multicenter, observational, retrospective, 16-weeks study, which included stable patients undergoing dialysis who were converted from DA QW to DA Q2W in clinical practice. Conversion was done according to product specifications (duplicating QW dose). The ERI to DA was calculated by dividing the weekly DA dose per kilogram of weight (microg/wk.kg)*200 by the Hb level (g/dL). ERI evolution with time was evaluated by multivariate repeated measures ANOVA, adjusting for significant covariates. A total of 202 patients were included (137 patients undergoing haemodialysis [HD], intravenous (IV) DA, and 65 patients receiving peritoneal dialysis [PD], subcutaneous DA). Mean (SD) age was 66 (17) years; 61% of patients were men. Large intercentre variability was observed for the ERI at conversion time (coefficient of variation of 88%, p < 0.001 for differences between centres). In the univariate analysis, predictor factors for high baseline ERI were low albumin level (r = -0.29; p =0.001), HD (mean ERI of 9.3 [8.4] vs 6.8 [4.6] for PD; p = 0.005), or previous cardiovascular disease (9.9 [8.7] vs 7.4 [6.3] for patients without history; p =0.025). During the follow up, the ERI was slightly increased in HD patients (9.3 [8.4] at conversion vs 11.1 [7.3] at 16 weeks; p < 0.05), and remained stable in PD patients (6.8 [4.6] vs 6.7 [4.0], respectively; NS). In the multivariate analysis, there were no significant differences in ERI during the 16 weeks post-conversion after adjusting for albumin levels and centre (adjusted baseline mean [95% CI] of 10.0 [8.7-11.4] vs 10.5 [9.3-11.8] at 16 weeks, adjusted change of +0.5 [-0.67; 1.67]; NS). After 16 weeks, only 7 patients (3.5%) had discontinued Q2W administration. Extension from weekly to once every other-week darbepoetin alpha allows to simplify anaemia treatment without increasing the resistance index, regardless of dialysis type. The multivariate analysis shows that, after adjusting by center and inflammation/nutritional status, there were no changes in the response to darbepoetin alpha during the first 16 weeks after conversion in clinical practice.

Dose Conversion Ratio one year after Switching from Epoetin Alpha to Darbepoetin Alpha in Japanese Hemodialysis Patients

Darbepoetin alpha is effective for renal anemia when epoetin is insufficient. We previously reported that the dose conversion ratio from epoetin alpha to darbepoetin alpha was 1:350.5 after 24 weeks of follow-up. This study assessed the conversion ratio in stable Japanese hemodialysis patients after 52 weeks. A total of 104 hemodialysis patients who were stable on intravenous epoetin alpha were switched to intravenous darbepoetin alpha according to the 1:200 rule. Then they were followed for 52 weeks to assess changes of hemoglobin and the darbepoetin alpha dose. Eighty-five patients completed the study. Their hemoglobin increased very rapidly during the first 8 weeks. The final conversion ratio was 1:286.6 at 52 weeks. Darbepoetin alpha showed similar efficacy in diabetics and non-diabetics. Patients switching from a high epoetin alpha dose (> or =4500 IU/week) had a higher conversion ratio compared with those switching from a low dose (<4500 IU/week). The dose conversion ratio of 1:200 was unsuitable and led to a rapid increase of hemoglobin. A conversion ratio of 1:250 to 1:300 should be employed when switching from epoetin alpha to darbepoetin alpha in Japanese patients.

Cost minimisation analysis for darbepoetin alpha vs epoetin alpha in chronic kidney disease patients on haemodialysis

IntroductionMultiple studies have shown that epoetin alpha (r-HuEpo) and darbepoetin alpha (NESP) are similarly effective and safe for maintaining haemoglobin levels in patients with chronic kidney disease (CKD). Nevertheless, there is some debate over their cost-effectiveness. The purpose of this study is to carry out a cost-minimisation analysis including a comparison of the costs to the hospital arising from treatment with r-HuEpo vs NESP. MethodsProspective observational study. We included CKD patients on haemodialysis with no iron, vitamin B12 or folate deficiencies, treated with stable doses of IV r-HuEpo. Follow-up was performed over three periods: the first during six months, maintaining prior treatment with r-HuEpo; the second for eight months, after changing to NESP, and the third, during the final eight months, following resuming r-HuEpo treatment. For converting both treatments, the conversion factor established on technical sheet 1:200 was used. ResultsFifty five patients completed the study and were valid for analysis. Their mean age was 68.3 years, and 18 were women (35.3%). The mean weekly doses at the end of each period were 8,058.8 (SD 3,911.1) IU for the EPO 1 period, 39.4 (SD 21.6) mg for NESP and 7,882.4 (SD 4,594.1) IU for EPO 2. The weekly costs for each treatment showed significant differences between NESP and r-HuEpo: the cost of NESP was higher. ConclusionIn our study, we found that r-HuEpo and NESP were similarly effective in patients with CKD on haemodialysis, but that there was a significant cost increase associated with NESP treatment.

Modification of gene expression: Help to detect doping with erythropoiesis‐stimulating agents

Enhanced oxygen delivery to tissues has been shown to improve endurance performance [1]. This has led to widespread abuse of erythropoiesis-stimulating agents (ESA) in elite sport. It is conceivable that athletes have even learned how to continue illicit ESA doping [2]. This possibility has fuelled the search for novel methods to detect and deter ESA abuse using indirect markers. It is now widely accepted that drugs influence gene expression [3,4]. In this study, we envisage its use as a means to detect ESA doping. We obtained a global view of the transcriptome of total blood cells both before and after treatment with darbepoetin alpha using the serial analysis of gene expression (SAGE) method. In silico analysis identified 95 genes whose differential expression was subsequently tested by quantitative real-time polymerase chain reaction (PCR) in two athletes. The athletes were treated first with high doses of recombinant human erythropoietin (rHuEpo) to increase their hemoglobin concentration and then with microdoses to maintain the high concentration of hemoglobin. Significance analysis of microarrays (SAM) at a delta ratio greater than 1.5 indicated that 33 genes could be significant markers of ESA administration. Interestingly, when high and microdoses were taken into account together, five genes could still be considered as significant markers.

Fluctuations in haemoglobin levels in haemodialysis, pre‐dialysis and peritoneal dialysis patients receiving epoetin alpha or darbepoetin alpha

To characterize the haemoglobin variability of haemodialysis, peritoneal dialysis and pre-dialysis patients treated with either epoetin alpha or darbepoetin alpha in a clinical setting where treatment was administered according to current standard Australian practice. Data on haemodialysis, pre-dialysis and peritoneal dialysis patients were extracted from the Renal Anaemia Management database (RAM) from 1 January 2001 to 31 December 2004. The variance in haemoglobin was calculated from patient records with more than five haemoglobin observations over a period of at least 4 weeks following 9 weeks of therapy. A mixed-model was fitted to the within-patient variances and weighting was based on the number of observations minus 1 for each record. The mean within-patient variance in haemoglobin levels for i.v. administered erythropoietin-stimulating agents (IV) haemodialysis, s.c. administered erythropoietin-stimulating agents (SC) haemodialysis, predialysis (SC) and peritoneal dialysis (SC) patients receiving epoetin alpha were 9% (95% CI: 13% to 5%, P < 0.0001), 17% (95% CI: 32% to 0.2%, P = 0.047), 19% (95% CI: 27% to 11%, P < 0.0001) and 26% (95% CI: 33% to 18%, P < 0.0001) lower than that for patients receiving darbepoetin alpha. The mean haemoglobin levels for haemodialysis (IV), haemodialysis (sc) predialysis (SC) and peritoneal dialysis (SC) patients receiving darbepoetin alpha were 11.6 g/dL, 11.2 g/dL, 11.5 g/dL and 11.5 g/dL compared with 11.5 g/dL, 11.6 g/dL, 11.7 g/dL and 11.5 g/dL for patients receiving epoetin alpha. There was 9-26% greater within-patient fluctuation in haemoglobin levels in patients receiving darbepoetin alpha compared with epoetin alpha. The causes of haemoglobin fluctuations and the implications for patient outcomes and resource use require further study.

L-carnitine supplementation and EPO requirement in children on chronic hemodialysis

L-carnitine supplementation has been the subject of heated discussion in the context of the treatment of pediatric hemodialysis patients. The aim of this study was to analyze the effect of intravenous L-carnitine supplementation on the erythropoetin (EPO) requirement in six pediatric hemodialysis patients. All patients were on intravenous L-carnitine (2.5 g per session for patients >30 kg and 1 g for those <30 kg) for 9 months. The EPO dose was adapted monthly to maintain a target hemoglobin (Hb) level of 11-13 g/dl. Prior to the initiation of L-carnitine supplementation, the EPO requirement was 1.15 +/- 0.22 (range 0.37-1.75) microg/kg darbepoetin alpha. Free carnitine (FC) levels were measured before (40.4 +/- 4.9 micromol/l), immediately after the 9-month L-carnitine supplementation period (378.5 +/- 77.3 micromol/l), and 4 months after withdrawal of L-carnitine (95.6 +/- 4.0 micromol/l). After 9 months, the EPO dose was 0.47 +/- 0.10 microg/kg (p < 0.002). The Hb levels increased from 12.2 +/- 0.97 to 14.0 +/- 0.54 g/dl (p < 0.05) within the first 2 months, and the EPO dose was then decreased in a stepwise manner. In conclusion, following intravenous carnitine supplementation, FC levels were higher and persisted longer than expected. This rise was associated with increased Hb levels and decreased EPO requirement. Since controls were missing for this study, prospective long-term multi-center studies on a large number of patients are required to provide solid answers to the controversial question of L-carnitine supplementation in hemodialyzed children.

Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data.

Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients. We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials. We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint. A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42). ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

Randomized study of darbepoetin alfa as modifier of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): Final outcome of the DAHANCA 10 trial

6007 Background: The study aimed to evaluate if correction of low hemoglobin (Hb) levels by means of the erythropoietin stimulating agent: darbepoetin alpha (Aranesp) during radiotherapy (RT) improves outcome in patients with HNSCC. Following a planned interim analysis which showed inferiority of the experimental treatment, the trial was stopped in November 2006. Methods: Pts with HNSCC eligible for primary RT alone and with Hb values below 14.0 g/dl were randomized to receive Aranesp together with accelerated fractionated RT. Pts. were stratified according to gender, T and N staging, tumor site, and institution. Aranesp was given subcutaneously in a dose of 150 micrograms weekly during RT, or stopped earlier if the Hb exceeded 15.5 g/dl. Results: In total, 522 patients (of a planned intake of 600) were included at the time of the interim analysis. Of these 514 pts were eligible for analysis (255 pts treated with Aranesp and 259 pts in the control group) with a median follow up of 49 months. Among these, 201 developed a loco-regional failure (primary endpoint). There have been 238 deaths of which 176 are due to HNSCC. The patients were evenly distributed according to the stratification parameters (gender, T and N staging, tumor site, institution).Aranesp resulted in the expected increase in Hb in more than 81% of the patients. The compliance to Aranesp was good with no significant difference in serious (cardiovascular) adverse events (3% vs. 1%). Overall, the results showed a poorer outcome in 5-year loco-regional control (59% vs. 68% (p = 0.04, RR: 1.47 [1.14–1.94]) for the Aranesp vs. control arm. This was also seen for the endpoint of disease-free survival (37% vs. 47%, p = 0.02, RR: 1.32 [1.04–1.68]), whereas there was no significant difference in overall survival (40% vs. 51%, p = 0.16, RR: 1.20 [0.93–1.55]). There were no differences in radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. Conclusions: Correction of the Hb level with Aranesp in patients with HNSCC resulted in a significantly poorer tumor control after radiotherapy. The treatment principle was abandoned and the difference in outcome is being subjected to further examination. No significant financial relationships to disclose.

DARBEPOETIN α, A LONG-ACTING ERYTHROPOEITIN DERIVATE, DOES NOT ALTER LPS EVOKED MYOCARDIAL DEPRESSION AND GENE EXPRESSION OF BAX, BCL-XS, BCL-XL, BCL-2, AND TNF-α

Darbepoetin alpha (DA), a long-acting erythropoietin derivative stimulating erythropoiesis, can, by antiapoptotic effects, mitigate myocardial I/R injury. We tested the hypothesis that DA treatment improves left ventricular function (LV) in LPS evoked cardiomyopathy and alters gene expression of apoptosis-regulating proteins (Bcl-XL, Bcl-2, Bax, and Bcl-Xs) and TNF-alpha. In a prospective, controlled, randomized study in Lewis rats (n = 56; 8 groups), myocardial depression was evoked by LPS administration (serotype O127:B8; 10 mg/kg, i.p.). Darbepoetin alpha or vehicle was injected either 24 h before (pretreatment) or 2 h after LPS injection (treatment). Hearts were isolated 8 h after LPS injection, perfused (Krebs-Henseleit solution) in a Langendorff apparatus, and LV developed pressure and its derivatives were measured. For gene expression analysis, real-time polymerase chain reaction of LV specimen was performed. LPS decreased LV developed pressure (-64.6 +/- 7.9 mmHg) and its derivates by more than 60% in comparison to vehicle (P < 0,01), but this effect was not attenuated by DA pretreatment or DA treatment. LPS administration increased gene expression of Bcl-Xs, Bax, and TNF-alpha, but this was not altered by DA pretreatment. Furthermore, there was no effect on Bcl-Xl and Bcl-2 expression by DA alone. Whereas proapoptotic genes of the myocardium are up-regulated in LPS-induced cardiomyopathy, neither DA pretreatment nor treatment has significant effects on LV function or gene expression. This may suggest cardiac resistance to darbepoetin in LPS-mediated sepsis.

Probabilistic cost-minimisation analysis of darbepoetin alpha versus epoetin alpha in treating anaemia secondary to chronic renal failure. Assessment in Spanish clinical practice

IntroductionThe direct transfer of the results of pharmaco-economic studies between countries may not be suitable if the proper adaptations are not made to take into account differences in treatment patterns, resource use, and costs from country to country. ObjectiveTo estimate the cost in Spain of treating anaemia secondary to chronic renal failure with darbepoetin alpha or epoetin alpha from a review and analysis of available current information. In addition, the role of the route of administration as a main driver of the cost will be analysed. MethodPopulation: patients with chronic renal failure induced anaemia. Data: Medline and Embase search of studies directly comparing erythropoiesis stimulating agents. Analysis: Cost minimization analysis from the perspective of a hospital pharmacy department. The main outcome chosen was the difference between the average cost per patient undergoing a 30-day treatment with epoetin alpha versus darbepoetin alpha. Resultsa) Haemodialysis: changing from epoetin alpha to darbepoetin alpha is associated with a cost reduction of 8.67%; 95% CI, −1.34 to 17.92 (€uro17.48; 95% CI, −2.70 to 36.13); probabilistic analysis showed that the use of darbepoetin alpha could be associated with a costsaving probability of 94.9%. The IV administration yielded a decrease in costs of about 16.00%; 95% CI, −2.38 to 36.77 (€uro41.78, 95% CI: −6.21 to 96.04); b) Pre-dialysis: darbepoetin alpha is associated with a cost reduction of about 11%–32%. ConclusionsThe use of darbepoetin alpha for the treatment of chronic renal failure induced anaemia (haemodialysis and pre-dialysis) shows higher cost efficiency than epoetin alpha in Spain; these differences increase with IV administration.

Pretreatment with Darbepoetin Attenuates Renal Injury in a Rat Model of Cisplatin-Induced Nephrotoxicity

Background/AimsDarbepoetin alfa (DPO) exhibits comparable renoprotective effects to erythropoietin (EPO) in several animal models of acute renal injury. We examined whether DPO also attenuated renal injury in a rat model of cisplatin nephrotoxicity.MethodsMale Spague-Dawley rats were divided into four groups: untreated, DPO-treated, cisplatin-injected, and DPO-treated cisplatin-injected. DPO pretreatment was conducted 24 hours after and just before cisplatin administration. Ninety-six hours after cisplatin administration, animals in all experimental groups were sacrificed. We examined serology; real-time reverse transcription polymerase chain reaction (RT-PCR) for TNF-α, Bcl-2, and MCP-1 gene expression; and Western blots for caspase-3. We also conducted terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and light microscopy.ResultsPretreatment with DPO significantly reduced the levels of blood urea nitrogen and serum creatinine, the magnitude of renal tubular epithelial damage, and renal gene expression of TNF-α, Fas, and MCP-1 in kidneys injured by cisplatin. Pretreatment with DPO significantly increased Bcl-2 mRNA levels in kidneys injured by cisplatin, and significantly reduced activated caspase-3 and TUNEL-positive cells.ConclusionsDPO exhibits a renoprotective effect in experimental cisplatin-induced renal injury, the mechanism of which may involve DPO antiinflammatory and antiapoptotic effects.

Switching from Epoetin Alpha to Darbepoetin Alpha in Japanese Hemodialysis Patients: Dose Conversion Ratio

Background/Aims: Darbepoetin alpha is an erythropoietic agent with a 3-fold longer elimination half-life than epoetin. The recommended conversion ratio from epoetin to darbepoetin alpha is 1:200 (1 μg of darbepoetin alpha = 200 IU of epoetin), but several observations have suggested that this ratio overestimates the required dose of darbepoetin alpha. This study assessed the actual conversion ratio for stable Japanese hemodialysis patients and investigated whether darbepoetin alpha promotes uniform erythropoiesis. Methods: A total of 104 hemodialysis patients who were stable on epoetin alpha therapy at Hakuai Clinic in Japan were switched to intravenous darbepoetin alpha according to the 1:200 rule. They were followed for 24 weeks to assess changes of hemoglobin and the dose of darbepoetin alpha, as well as changes of the reticulocyte count. Results: One hundred patients completed the 24-week study and the final conversion ratio was 1:350.5. Darbepoetin alpha showed a similar effect in diabetics and nondiabetics. Data on the reticulocyte count demonstrated that darbepoetin alpha had a sustained effect on erythropoiesis. Conclusion: Darbepoetin alpha is effective for Japanese dialysis patients at a lower dose than expected.

Anemia, chronic renal disease and chronic heart failure: the cardiorenal anemia syndrome

SUMMARYThe mortality and morbidity of congestive heart failure (CHF) have improved slightly over the years but are still very high. Many patients with CHF are anemic, which raises the question, ‘Could uncontrolled anemia be a cause?’ The anemia is associated with more severe CHF and higher mortality, hospitalization and morbidity rates. The only way to prove that anemia is causing this worsening of CHF is to correct it. We review here some of the published papers about correction of anemia. Many, but not all, show a positive effect of erythropoietin or its derivatives when coadministered with oral or intravenous (IV) iron, with improvements in left and right ventricular systolic and diastolic function, dilation, hypertrophy, renal function, New York Heart Association class, exercise capacity, oxygen utilization, caloric intake, quality of life, and the activity of endothelial progenitor cells. A reduction in hospitalizations, diuretic dose, pulmonary artery pressure, plasma volume, heart rate, serum brain natriuretic peptide levels, the inflammatory marker interleukin 6, and soluble Fas ligand (a mediator of apoptosis) were also observed. Iron deficiency may also play an important role in this anemia because improvement in CHF has been seen with IV iron treatment alone. We call the interaction between chronic renal failure, CHF and anemia the cardiorenal anemia syndrome. Each of these three elements causes or exacerbates the others, and their correction can prevent the progression of both renal and heart failure. However, until ongoing large placebo‐controlled studies on darbepoetin alpha or IV iron are completed, we will not know whether these treatments really influence the outcome of renal failure and CHF.

Darbepoetin Alpha is Highly Cost‐effective Compared With Epoetin Alpha in the Treatment of Renal Anemia: A Brief Report From a Hemodialysis Clinic in Japan

Darbepoetin Alpha is Highly Cost‐effective Compared With Epoetin Alpha in the Treatment of Renal Anemia: A Brief Report From a Hemodialysis Clinic in Japan

Darbepoetin-alpha prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure.

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.

Population pharmacokinetics of darbepoetin alfa in peritoneal dialysis and non-dialysis patients with chronic kidney disease after single subcutaneous administration

To characterize the pharmacokinetics of darbepoetin alpha and covariate relationships in chronic kidney disease (CKD) patients after a single subcutaneous administration. A total of 989 serum concentration recordings from 64 patients were analyzed using NONMEM with a model including endogenous erythropoietin production. The basic and final models were evaluated for stability using bootstrapping. The selected basic model had one-compartment with a combination of the additive and constant coefficient of variation error models for residual variability. The significant covariate was weight for apparent clearance (CL/f) and apparent volume of central compartment (V(1)/f). The typical values of CL/f, V(1)/f, and absorption rate constant were 0.158 l/h, 13.7 l, and 0.0376/h, respectively. Evaluation by bootstrapping showed that the final model was stable. The present analysis indicated that weight is a significant covariate for CL/f and V(1)/f. However, dosage adjustment according to weight is not necessary for subcutaneous administration of darbepoetin alpha in CKD patients.

A proposal of the simple guide regarding the conversion ratio from epoetin to darbepoetin alpha in treating haemodialysis patients with renal anaemia.

A proposal of the simple guide regarding the conversion ratio from epoetin to darbepoetin alpha in treating haemodialysis patients with renal anaemia.