losartan-potassium and Renal-Insufficiency--Chronic

As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD).. Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs).. Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively).. Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

The production of erythropoietin (EPO), the main regulator of erythroid differentiation, is regulated by hypoxia-inducible factor (HIF). HIF2α seems to be the principal regulator of EPO transcription, but HIF1α and 3α also may have additional influences on erythroid maturation. HIF is also involved in the regulation of iron, an essential component in erythropoiesis. Iron is essential for the organism but is also highly toxic, so its absorption and retention are strictly controlled. HIF also induces the synthesis of proteins involved in iron regulation, thereby ensuring the availability of iron necessary for hematopoiesis. Iron is a major component of hemoglobin and is also involved in erythrocyte differentiation and proliferation and in the regulation of HIF. Renal anemia is a condition in which there is a lack of stimulation of EPO synthesis due to decreased HIF expression. HIF prolyl hydroxylase inhibitors (HIF-PHIs) stabilize HIF and thereby allow it to be potent under normoxic conditions. Therefore, unlike erythropoiesis-stimulating agents, HIF-PHI may enhance iron absorption from the intestinal tract and iron supply from reticuloendothelial macrophages and hepatocytes into the plasma, thus facilitating the availability of iron for hematopoiesis. The only HIF-PHI currently on the market worldwide is roxadustat, but in Japan, five products are available. Clinical studies to date in Japan have also shown that HIF-PHIs not only promote hematopoiesis, but also decrease hepcidin, the main regulator of iron metabolism, and increase the total iron-binding capacity (TIBC), which indicates the iron transport capacity. However, concerns about the systemic effects of HIF-PHIs have not been completely dispelled, warranting further careful monitoring.

Topics: Anemia; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Procollagen-Proline Dioxygenase; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Hypoxia-inducible factor (HIFs) is a new class of drug developed for the management of anemia in chronic kidney disease (CKD) patients. HIFs increase the production of erythropoietin in the kidney and liver, enhance the absorption and utilization of iron, and stimulate the maturation and proliferation of erythroid progenitor cells. Besides, HIFs regulate many physiologic processes by orchestrating the transcription of hundreds of genes. Essential hypertension (HT) is an epidemic worldwide. HIFs play a role in many biological processes involved in the regulation of blood pressure (BP). In the current review, we summarize pre-clinical and clinical studies investigating the relationship between HIFs and BP regulation in patients with CKD, conflicting issues, and discuss future potential strategies.

Topics: Anemia; Erythropoietin; Essential Hypertension; Humans; Hypoxia; Kidney; Renal Insufficiency, Chronic

Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses.. A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted. Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety.. HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Humans; Hypoxia; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that enarodustat corrected and maintained hemoglobin (Hb) levels by stimulating endogenous erythropoietin production and improving iron utilization in anemic patients with chronic kidney disease, regardless of whether they were on dialysis. In addition, Phase III comparative studies demonstrated that enarodustat was noninferior to darbepoetin alfa in controlling Hb levels. Furthermore, enarodustat was well tolerated during the treatment. Enarodustat is currently being developed in the Republic of Korea and China and is expected to be developed worldwide. This article reviews the data on enarodustat, including the findings from preclinical studies, pharmacokinetics/pharmacodynamics, and efficacy and safety results of clinical studies.

Topics: Anemia; Erythropoietin; Hematinics; Humans; N-substituted Glycines; Prolyl-Hydroxylase Inhibitors; Pyridines; Renal Insufficiency, Chronic; Triazoles

Renal erythropoietin (Epo)-producing (REP) cells represent a rare and incompletely understood cell type. REP cells are fibroblast-like cells located in close proximity to blood vessels and tubules of the corticomedullary border region. Epo mRNA in REP cells is produced in a pronounced "on-off" mode, showing transient transcriptional bursts upon exposure to hypoxia. In contrast to "ordinary" fibroblasts, REP cells do not proliferate ex vivo, cease to produce Epo, and lose their identity following immortalization and prolonged in vitro culture, consistent with the loss of Epo production following REP cell proliferation during tissue remodelling in chronic kidney disease. Because Epo protein is usually not detectable in kidney tissue, and Epo mRNA is only transiently induced under hypoxic conditions, transgenic mouse models have been developed to permanently label REP cell precursors, active Epo producers, and inactive descendants. Future single-cell analyses of the renal stromal compartment will identify novel characteristic markers of tagged REP cells, which will provide novel insights into the regulation of Epo expression in this unique cell type.

Topics: Animals; Erythropoietin; Hypoxia; Kidney; Mice; Mice, Transgenic; Renal Insufficiency, Chronic; RNA, Messenger

Anemia is a common medical problem among patients with cancer and chronic kidney disease (CKD). Although anemia in patients with CKD is often treated with iron and erythropoietin-stimulating agents, there are controversies with regard to the use of erythropoietin-stimulating agents in cancer patients. In this article, we review the treatment of anemia in patients with cancer and CKD, in addition to summarizing the current guidelines in treatment of anemia in these patients.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms; Renal Insufficiency, Chronic

Desidustat (Oxemia™) is an orally bioavailable, small molecule, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor developed by Zydus Cadila for the treatment of anaemia associated with chronic kidney disease (CKD), COVID-2019 infections and chemotherapy induced anaemia. Desidustat inhibits prolyl hydroxylase domain enzymes, resulting in the stabilisation of hypoxia-inducible factor which stimulates erythropoietin production and erythropoiesis. In March 2022, desidustat received its first approval in India for the treatment of anaemia in adults with CKD who are either on dialysis or not on dialysis. Desidustat is in clinical development in China for the treatment of anaemia in patients with CKD, in Mexico for the management of COVID-2019 infections and in the USA for the treatment of chemotherapy induced anaemia. This article summarizes the milestones in the development of desidustat leading to this first approval for anaemia associated with CKD.

Topics: Adult; Anemia; Antineoplastic Agents; COVID-19 Drug Treatment; Erythropoietin; Humans; Hypoxia; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Quinolones; Renal Insufficiency, Chronic

The aging of the population has led to an increased prevalence of chronic diseases such as chronic kidney disease. Anemia is one of the most frequent complications of chronic kidney disease, with an impact not only on the quality of life but also on the patient's prognosis and associated costs. Knowledge in this therapeutic area has increased significantly: from the appearance of recombinant erythropoietin in 1989, through the use of increasing doses of parenteral iron and, more recently, to new molecules such as hypoxia-inducible factor inhibitors. The aim of this article is to present a pragmatic review of the state of the art in the epidemiology, pathophysiology, diagnosis and treatment of anemia associated with chronic kidney disease.. O envelhecimento populacional tem-se traduzido no aumento de prevalência de doenças crónicas como a doença renal crónica. A anemia é uma das complicações mais frequentes da doença renal crónica, com impacto não só na qualidade de vida como no prognóstico do doente e nos custos associados. O conhecimento nesta área terapêutica tem aumentado de forma significativa: desde o aparecimento da eritropoietina recombinante em 1989, passando pelo uso de doses crescentes de ferro parentérico e, mais recentemente, a novas moléculas como os inibidores do hypoxia-inducible factor. Os autores pretendem rever, de uma forma pragmática, o estado da arte da anemia associada à doença renal crónica, desde a epidemiologia, à fisiopatologia, ao diagnóstico e ao tratamento.

Topics: Anemia; Erythropoietin; Humans; Iron; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Insufficiency, Chronic

Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients.. A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021.. Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to  - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model.. HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

Topics: Anemia; Erythropoietin; Hepcidins; Humans; Hypoxia; Iron; Prolyl-Hydroxylase Inhibitors; Receptors, Transferrin; Renal Dialysis; Renal Insufficiency, Chronic; Transferrin; Triglycerides

Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESAs) and iron. Experimental studies extensively investigated the mechanisms involved in the body's response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESAs. Overall, data from phases 2 and 3 clinical development showed efficacy in anemia correction and maintenance for all of the class molecules compared with placebo (superiority) or erythropoiesis-stimulating agents (noninferiority). Three molecules, roxadustat, vadadustat, and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular end points, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the nondialysis population, at the prespecified primary analyses, all three molecules met the noninferiority margin for the risk of major cardiovascular events compared with erythropoiesis-stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared with already available ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Renal Insufficiency, Chronic

Diabetes is one of the leading causes of chronic kidney disease (CKD), and multiple underlying mechanisms involved in pathogenesis of diabetic nephropathy (DN) have been described. Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden, considering that about 40% of type 2 diabetes patients will develop nephropathy. In the past years, some research found that hypoxia response and hypoxia-inducible factors (HIFs) play critical roles in the pathogenesis of DN. Hypoxia-inducible factors (HIFs) HIF-1, HIF-2, and HIF-3 are the main mediators of metabolic responses to the state of hypoxia, which seems to be the one of the earliest events in the occurrence and progression of diabetic kidney disease (DKD). The abnormal activity of HIFs seems to be of crucial importance in the pathogenesis of diseases, including nephropathies. Studies using transcriptome analysis confirmed by metabolome analysis revealed that HIF stabilizers (HIF-prolyl hydroxylase inhibitors) are novel therapeutic agents used to treat anemia in CKD patients that not only increase endogenous erythropoietin production, but also could act by counteracting the metabolic alterations in incipient diabetic kidney disease and relieve oxidative stress in the renal tissue. In this review, we present the newest data regarding hypoxia response and HIF involvement in the pathogenesis of diabetic nephropathy and new therapeutic insights, starting from improving kidney oxygen homeostasis.

Topics: Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Humans; Hypoxia; Oxygen; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia of chronic kidney disease (CKD) has traditionally been treated with recombinant human erythropoietin (rhEPO). Recently, daprodustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor, has also been shown to increase hematocrit. It remains unclear whether daprodustat or rhEPO should be the treatment of choice for anemia of CKD. We aimed to assess the efficacy and cardiovascular safety of daprodustat versus rhEPO in CKD patients.. Online databases were queried in April 2022 for articles comparing the efficacy and safety of daprodustat in DD-CKD and NDD-CKD subgroups. Results from trials were pooled using a random-effects model.. Data on 8245 CKD patients from eight clinical trials were included. Our results show that in comparison to rhEPO, daprodustat maintained the same efficacy in increasing hemoglobin levels in both the DD-CKD (MD: 0.10; 95% CI [- 0.13,0.34]; p = 0.50) and NDD-CKD (MD: - 0.01; 95% CI [- 0.38,0.35]; p = 0.95) subgroups. Daprodustat significantly lowered hepcidin levels and significantly increased TIBC in both subgroups. Additionally, daprodustat significantly reduced the incidence of major adverse cardiovascular events (MACE) (RR: 0.89; 95% CI: 0.89-0.98; p = 0.02) and its myocardial infarction (MI) component (RR: 0.74; 95% CI: 0.59-0.92; p = 0.006) in the DD-CKD subgroup.. Daprodustat has similar efficacy compared to rhEPO for the treatment of anemia of CKD. On treatment, the reduced experience of MACE was reported in DD-CKD patients as compared to rhEPO. Furthermore, effects on iron metabolism varied by parameter, with daprodustat being superior to rhEPO in some cases and inferior in others.

Topics: Anemia; Barbiturates; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Iron; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Insufficiency, Chronic

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular Diseases; Enzyme Inhibitors; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Renal Insufficiency, Chronic

Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Insufficiency, Chronic

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

Topics: Acute Kidney Injury; Erythropoiesis; Erythropoietin; Homeostasis; Humans; Inflammation; Iron; Iron-Regulatory Proteins; Kidney; Kidney Tubules, Distal; Kidney Tubules, Proximal; Mitochondria; Nephrons; Oxidative Stress; Renal Insufficiency, Chronic

Topics: Anemia; Anemia, Iron-Deficiency; Erythropoietin; Humans; Renal Insufficiency, Chronic; Risk Factors

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient's life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all.

Topics: Anemia; Animals; Antioxidants; Cytokines; Erythropoietin; Humans; Inflammation; Renal Insufficiency, Chronic

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are orally active small molecules and are launched as novel therapeutic agents for anemia in chronic kidney disease (CKD). In contrast to conventional exogenous erythropoietin (EPO) administration, HIF-PHIs stimulate endogenous EPO production and improve iron metabolism via stabilization of hypoxia-inducible factor (HIF). This review summarizes the mechanism of action, the results of clinical trials, and future perspectives of HIF-PHIs.. Six HIF-PHIs are currently under phase III studies, some of which have been already completed. According to the results of clinical trials, HIF-PHIs increased and maintained hemoglobin levels in both nondialysis-dependent and dialysis-dependent CKD patients with physiological EPO concentrations. HIF-PHIs also improved iron utilization and were comparably effective regardless of underlying inflammation and iron status.. HIF-PHIs have several advantages including oral administration, physiological EPO secretion, and improved iron utilization. Undoubtedly, HIF-PHIs will pave the new way in the field of treatment of anemia in CKD, but it should be noted that HIFs have pleiotropic effects on a plethora of cellular functions, which might lead to either beneficial or undesirable off-target effects. Intensive postmarketing surveillance is crucially important to identify unexpected consequences.

Topics: Anemia; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) pathway is responsible for regulating the biosynthesis of erythropoietin (EPO) and maintaining iron homeostasis. Investigational drugs that target the HIF-PH pathway are promising alternatives for treating anemia in Chronic Kidney Disease (CKD).. This review summarizes recent advances focused on the clinical development of HIF-PH inhibitors (HIF-PHIs) as potentially novel therapies in the treatment of anemia in CKD based on publications available on PubMed and restricted Google searches. We provide a comparison between HIF-PHIs regarding their pharmacokinetics, dosing regimens and safety concerns, structure-activity relationships, and alterations in key laboratory parameters observed in animal models and clinical trials.. HIF-PHIs may be advantageous in some aspects compared to the conventional erythropoiesis-stimulating agents (ESAs). While ESAs could increase the risk of cardiovascular events due to rapid rises in ESA blood levels, HIF-PHIs have been reported to maintain EPO concentrations at levels that are closer to the normal physiological ranges. Although HIF-PHIs have been demonstrated to be relatively safe and effective in clinical trials, long-term safety data are needed in order to establish whether these therapeutic agents will lead to a major paradigm change in the treatment of anemia of CKD.

Topics: Anemia; Animals; Drugs, Investigational; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

Topics: Anemia; Erythropoietin; Hematinics; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties.. A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020).. Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; COVID-19; Epoetin Alfa; Erythropoietin; Expert Testimony; Forecasting; Guideline Adherence; Hematinics; Hematologic Neoplasms; Hematopoiesis; Humans; Iron; Medicine; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Ischemia; Neoplasms; Observational Studies as Topic; Pandemics; Practice Guidelines as Topic; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Renal Dialysis; Renal Insufficiency, Chronic; SARS-CoV-2; Venous Thromboembolism

Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Prognosis; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia is the major complication resulting from chronic kidney disease (CKD) and also a risk factor for cardiovascular events and a poor quality of life (QoL). Diabetic kidney disease (DKD) is the major cause of CKD. Initially, insulin resistance has been reported to increase erythropoiesis, but it might be a minor issue. DKD-related anemia developed earlier and was more severe than non-DKD-related anemia based on more complicated mechanisms, including greater bleeding tendency associated with antiplatelet effect, less O2 sensing due to autonomic neuropathy or renin-angiotensin-aldosterone system inhibitor use, inhibitory effect of inflammatory cytokines, urinary loss of erythropoietin (EPO), and poor response to EPO. In DKD patients, prompt correction of anemia allows for a better cardiovascular outcome and QoL, which are similar to the promising effect of anemia correction in CKD patients. However, current evidence recommended that the avoidance of a high or normalized hemoglobin (Hb) level has been suggested in the treatment of anemia in DKD patients. Despite that EPO has a pleotropic effect on renal protection from animal studies, the renal benefit was less evident in CKD and DKD patients. Recently, the antidiabetic agent, sodium glucose cotransporter-2 inhibitors (SGLT2i), has been reported to exhibit the renal benefits due to the tubulo-glomerular feedback in addition to sugar control. It may also be due to less renal ischemic through higher EPO levels, followed by higher Hb levels. More studies are needed to clarify the link between the renal benefit of SGLT2i and EPO production.

Topics: Anemia; Diabetic Nephropathies; Erythropoietin; Humans; Renal Insufficiency, Chronic

Prolyl-hydroxylase inhibitors are a novel class of orally administered drugs that are under development for the treatment of anemia in patients with chronic kidney disease. This review discusses the biology of these drugs and their target - hypoxia-inducible factor and potential advantages and disadvantages of these therapies. Finally, we will discuss current trials in patients with both chronic kidney disease and end-stage renal disease.. Recent smaller studies have found that prolyl-hydroxylase are as effective as erythropoietin in treating anemia of chronic kidney disease. We do not yet know if they have the same cardiovascular and cancer-related risk profile and these questions will be answered by large phase III trials that are ongoing.. Although prolyl hydroxylase inhibitors have much potential, questions remain regarding their efficacy and safety. Should these concerns prove to be unfounded, the treatment of anemia in chronic kidney disease will likely be transformed over the next decade.

Topics: Administration, Oral; Anemia; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Intracellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Mitochondrial Proteins; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Over the past two decades it has emerged that, in addition to erythropoietic activity, erythropoietin (EPO) has numerous other functions, including neuro-protective, anti-apoptotic, antioxidant, angiogenetic and immunomodulatory ones. EPO interacts with two different forms of its receptor (EPOR): a homodimer receptor, responsible for the erythropoietic effects, and a heterodimer receptor, responsible for the non-erythropoietic effects. The effects on the heterodimer receptor are responsible for EPO-induced prolongation of organ transplant survival in mice and humans. The development of new molecules that selectively target the heterodimer EPOR is allowing to test the effect of long-term treatments, without the possible complications related to the increased hematocrit.

Topics: Adaptive Immunity; Anemia; Animals; Cell Hypoxia; Erythropoiesis; Erythropoietin; Graft Survival; Heart; Humans; Immunity, Cellular; Immunity, Innate; Kidney; Mice; Nervous System; Organ Transplantation; Rats; Receptors, Colony-Stimulating Factor; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency, Chronic; Retina

Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolyl-hydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.

Topics: Adult; Age Factors; Anemia; Animals; Child; Clinical Trials, Phase III as Topic; Disease Models, Animal; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Proteolysis; Renal Insufficiency, Chronic; Signal Transduction; Treatment Outcome; Up-Regulation; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

Chronic kidney disease (CKD) is associated with several complications that worsen with progression of disease; anemia, disturbances in iron metabolism and inflammation are common features. Inflammatory response starts early, releasing pro-inflammatory cytokines, acute phase reactants and hepcidin. Hepcidin production is modulated by several factors, as hypoxia/anemia, erythropoietin and erythropoiesis products, transferrin saturation (TSAT) and liver iron levels, which are altered in CKD. Treatment of CKD anemia is based on pharmaceutical intervention, with erythropoietic stimulating agents and/or iron supplementation; however, in spite of the erythropoietic benefits, this therapy, on a regular basis, involves risks, namely iron overload. To overcome these risks, some therapeutic approaches are under study to target CKD anemia. Considering the actual alerts about risk of iron overload in dialysis patients, inhibition of hepcidin, the central key player in iron homeostasis, could be a pivotal strategy in the management of CKD anemia.

Topics: Anemia; Erythropoietin; Gene Expression Regulation; Hepcidins; Humans; Iron; Renal Insufficiency, Chronic

Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.

Topics: Adaptive Immunity; Calcitriol; Calcium; Epigenesis, Genetic; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gastrointestinal Microbiome; Hematopoietic Stem Cells; Humans; Immunity, Innate; Immunocompromised Host; Immunosenescence; Infections; Inflammation; Iron; Oxidative Stress; Parathyroid Hormone; Renal Insufficiency, Chronic; Renal Replacement Therapy; Renin; Renin-Angiotensin System; Vitamin D

Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and occurs due to diminished renal function. The main cause of such anemia is decreased erythropoietin (EPO) production and secretion from the kidney and a lower erythropoietic response to EPO. Treatment therefore involves erythropoiesis-stimulating agents (ESAs). Optimal erythropoietic response to ESA therapy also requires adequate iron management. However, iron metabolism is also dysregulated in CKD patients.. During erythropoiesis, biomarkers of iron metabolism are dramatically altered by ESA therapy. Hepcidin 25 is a key hormone of iron metabolism that regulates iron absorption from the gut and the release of stored iron out of reticuloendothelial system cells. Recently, erythroferrone has been identified as an erythroid suppressor of hepcidin 25 production. Because erythroferrone levels are significantly increased by ESA treatment in CKD patients, it may be a key factor in facilitating the release of stored iron into the circulation during erythropoiesis in these patients. In this review, we discuss the characteristics of the important biomarkers of iron metabolism in CKD patients and the changes in these biomarkers after ESA administration. Key Messages: In CKD patients, the management of anemia with ESA therapy requires comprehensive assessment of the levels of various biomarkers, with consideration of their optimal and physiological levels during erythropoiesis.

Topics: Anemia; Biomarkers; Erythropoiesis; Erythropoietin; Hematinics; Humans; Iron; Renal Insufficiency, Chronic

Topics: Adenosine Triphosphate; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Progression; Diuresis; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Glucose; Heart; Heart Failure; Hematocrit; Hemoglobins; Humans; Kidney; Kidney Tubules, Proximal; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Potassium-Exchanging ATPase; Sympathetic Nervous System

Recent research has revealed that regulation of the bone-secreted hormone fibroblast growth factor 23 (FGF23) is not limited to classical mineral factors. Specifically, bidirectional relationships have been described between FGF23 production and anemia, iron status, and inflammation. Here, we will review the latest published articles on the crosstalk between FGF23 and the aforementioned nonclassical factors.. It has been recently reported that erythropoietin, iron deficiency, and inflammation increase FGF23 production and metabolism. Moreover, FGF23 promotes anemia and regulates inflammatory responses. These findings are particularly important in the setting of chronic kidney disease which is characterized by elevated FGF23 levels and several associated comorbidities.. Regulation of FGF23 is complex and involves many bone and renal factors. More recently, erythropoietin, iron deficiency, and inflammation have been also shown to affect FGF23 transcription and cleavage. Importantly, FGF23 has emerged as a regulator of erythropoiesis, iron metabolism, and inflammation. These findings provide novel and important insights into the pathophysiologic mechanisms of chronic kidney disease and may present new opportunities for therapeutic clinical interventions.

Topics: Erythropoiesis; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Inflammation; Iron; Renal Insufficiency, Chronic

Several Erythropoiesis-stimulating agents (ESAs) are available to treat anemia in patients with chronic kidney disease (CKD). Questions about the comparability of such therapeutic options are not purely a regulatory or economical matter. Appropriate use of originator or biosimilar in these patients need to be supported by clinical data. Regarding the prevention of blood transfusion, reduction of fatigue, breathlessness and mortality or cardiovascular events, a summary of the comparative efficacy and safety data of these drugs is lacking.. We performed a systematic literature search of CENTRAL, PubMed, and Embase through November 11, 2015. Our inclusion criteria encompassed randomized, controlled clinical trials that evaluated the comparative effectiveness of different ESAs originators and/or biosimilar. The considered participants were adults aged 18 years or older with anemia due to CKD. The overall quality of evidence was assessed using the GRADE system.. We identified 30 eligible studies including 7843 patients with CKD, and 21/30 studies included patients using hemodialysis or peritoneal dialysis. Compared with ESA biosimilars, epoetin α did not statistically differ for any of the ten measured outcomes. The quality of evidence varied from low to very low. In the comparison between epoetin α vs. darbepoetin α, no differences were observed for all outcomes, but blood transfusions showed favorable results for darbepoetin α: RR 2.18 (1.31-3.62). The quality of evidence varied from low to very low. No differences were observed between epoetin β and methoxy polyethylene glycol-epoetin β, and between darbepoetin α and methoxy polyethylene glycol-epoetin β, the quality of evidence varied from moderate to very low.. Data from 31 included studies allowed to pool data in meta-analysis related to four different comparisons and eleven outcome measures. Nevertheless, only one result was statistically significant in favor of darbepoetin α in the comparison with epoetin α concerning blood transfusions. For all the other outcomes and comparisons, we did not find any differences in terms of efficacy and security between the EPO considered. The quality of evidence is quite low, and further research could change these results. Further high quality studies examining the comparative effectiveness of ESAs need to be conducted.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Blood Transfusion; Comparative Effectiveness Research; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

This article reviews an emerging therapeutic agent, which is currently in phase III development for the treatment of anemia secondary to chronic kidney disease, covering promising phase II results, drug characteristics, and the current phase III trials, which, if approved, may significantly impact the management of anemia in this patient population.

Topics: Anemia; Barbiturates; Clinical Trials, Phase III as Topic; Erythropoietin; Glycine; Humans; Renal Dialysis; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration

Anemia is a common complication and contributes to increased morbidity and mortality in chronic kidney disease (CKD) patients. Whereas there has been a significant improvement of understanding the underlying mechanism of erythropoiesis, the treatment of renal anemia is still restricted to erythropoietin (EPO)-stimulating agents. The purpose of this article is to review the physiology of erythropoiesis, functional role of EPO and underlying molecular and cellular basis that regulate EPO production. Regulation of EPO production is at mRNA level. When anemia or hypoxia occurs, transcriptional factor, hypoxia-inducible factor (HIF), binds to EPO 5' hypoxic response element and EPO gene transcription increases. The renal EPO is mainly produced by pericytes. In CKD, pericytes transdifferentiate to myofibroblasts, and subsequently the ability of EPO production decreases, leading to renal anemia. Recent experimental and clinical studies show the promising efficacy of prolyl hydroxylase inhibitors in renal anemia through increasing EPO production by stabilizing HIF. Recent advances on epigenetics create a new field to study EPO gene expression at chromatin level. We will discuss the role of demethylating agent on restoring EPO expression, providing a novel approach to the treatment of renal anemia.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1; Myofibroblasts; Pericytes; Renal Insufficiency, Chronic

First generation erythropoiesis stimulating agents (ESAs) have short duration of action which requires administration once weekly or greater. Second generation ESAs were developed which have longer duration of action and can be administered one to two times monthly. Erythropoietin (EPO) mimetic peptides (EMPs) activate the EPO receptor but have no structural analogy to EPO, offering the potential for lower cost as they are not biologic drugs. The first approved EMP, peginesatide, was withdrawn from the market within a year of its approval because of fatal anaphylactic reactions. In this review, we summarize recent progress regarding the development of newer, possibly less toxic, EMPs. We also summarize the development of EPO fusion proteins which fuse EPO with a portion of an immunoglobulin molecule or another EPO molecule, achieving a longer duration of action and less frequent dosing.. AGEM400(hydroxyethyl starch) and pegolsihematide are EMPs in phase II clinical trials. Three EPO fusion proteins are under development, two in phase I and one in phase II.. The future success of EMPs is limited by the prior experience with peginesatide and EPO fusion proteins do not offer cost savings or longer duration of action than currently available ESAs.

Topics: Anemia; Biosimilar Pharmaceuticals; Erythropoiesis; Erythropoietin; Hematinics; Humans; Hydroxyethyl Starch Derivatives; Peptides; Polyethylene Glycols; Receptors, Erythropoietin; Recombinant Fusion Proteins; Renal Insufficiency, Chronic

Historically, the identity of O2-sensing renal erythropoietin (Epo)-producing (REP) cells was a matter of debate. This review summarizes how recent breakthroughs in transgenic mouse and in-situ hybridization techniques have facilitated sensitive and specific detection of REP cells and accelerated advancements in the understanding of the regulation of renal Epo production in health and disease.. REP cells are a dynamically regulated unique subpopulation of tubulointerstitial cells with features of fibroblasts, pericytes and neurons. Under normal conditions, REP cells are located in the corticomedullary border region within a steep decrement in O2 availability. During the progression of chronic kidney disease (CKD), REP cells cease Epo production, dedifferentiate and contribute to the progression of renal fibrosis. However, CKD patients with renal anaemia still respond with elevated Epo production following treatment with hypoxia-mimicking agents.. We hypothesize that REP cells are neuron-like setpoint providers and controllers, which integrate information about blood O2 concentration and local O2 consumption via tissue pO2, and combine these inputs with intrinsic negative feedback loops and perhaps tubular cross-talk, converging in Epo regulation.

Topics: Anemia; Animals; Cell Dedifferentiation; Erythropoietin; Fibrosis; Humans; Kidney; Mice, Transgenic; Oxygen; Renal Insufficiency, Chronic

To discuss if there will still be a role for the originator ESAs after the already available biosimilars and the approval of HIF stabilizers in the near future.. Current treatment with erythropoiesis-simulating agents (ESAs) is effective and generally well tolerated, but requires parenteral injections. It is also surrounded by safety concerns and is still expensive. Functional iron deficiency is the major obstacle for efficient ESA therapy. ESA resistance may develop, calling for high ESA doses, further increasing the side effects associated with ESA use. Biosimilars were introduced for reducing costs. In searching for an ideal antianemic drug, new investigational strategies have been proposed including the attractive alternative hypoxia-inducible factor (HIF) stabilizers, which stimulate endogenous EPO production. However, we should caution in translating the historical results referring to the side effects of ESAs to current clinical practice, considering that hemoglobin targets and ESAs doses are now much lower. We could anticipate that side effects will be much less.. According to preliminary data, orally administered HIF stabilizers could provide pharmacological advantages over the existing ESAs. These will need confirmation by the findings of large, phase-3, clinical trials. Finally, cost will be an important issue determining their future use.

Topics: Anemia; Basic Helix-Loop-Helix Transcription Factors; Biosimilar Pharmaceuticals; Drug Administration Routes; Erythropoiesis; Erythropoietin; Hematinics; Humans; Iron; Recombinant Proteins; Renal Insufficiency, Chronic

Small-molecule inhibitors of prolyl hydroxylase domain enzymes (PHD inhibitors) are novel renal anemia therapies that increase endogenous erythropoietin (EPO) production by stabilizing hypoxia-inducible factor (HIF). This review summarizes recent findings and future perspectives of PHD inhibitors (HIF stabilizers) in chronic kidney disease (CKD)-associated anemia.. Clinical trials have demonstrated that HIF stabilizers effectively increase hemoglobin levels of both nondialysis and dialysis CKD patients without causing serious adverse effects. HIF stabilizers not only restore EPO production but also optimize iron metabolism by reducing hepcidin levels. Considering the pleiotropic roles of the PHD-HIF pathway, HIF stabilizers might have both advantageous and disadvantageous effects in humans, in addition to erythropoiesis. Results of studies in animal models have suggested that HIF stabilizers alleviate ischemia-reperfusion injury and play protective roles against metabolic diseases. In contrast, a theoretical concern exists regarding the potential for tumorigenesis due to HIF stabilization.. At least five HIF stabilizers are now in phase III trials and may appear on the market in 1-2 years. The long-term effects and safety of HIF stabilization should be carefully examined in future basic and clinical studies.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Erythropoietin; Humans; Kidney; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Hypoxia is a common clinical problem that has profound effects on renal homeostasis. Prolyl-4-hydroxylases PHD1, 2 and 3 function as oxygen sensors and control the activity of hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor that regulates a multitude of hypoxia responses, which help cells and tissues to adapt to low oxygen environments. This review provides an overview of the molecular mechanisms that govern these hypoxia responses and discusses clinical experience with compounds that inhibit prolyl-4-hydroxylases to harness HIF responses for therapy in nephrology.

Topics: Erythropoietin; Homeostasis; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Oxygen; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia is a common complication of chronic kidney disease and is mainly caused by the inability of injured kidneys to produce adequate amounts of erythropoietin. Studies elucidating the regulation of erythropoietin production led to the identification of hypoxia-inducible factor (HIF), which activates the transcription of genes that mediate adaptive responses to hypoxia. HIF is a heterodimer that consists of an α and β subunit. While HIF-β is constitutively expressed, HIF-α is subjected to ubiquitination and proteasomal degradation under normoxic conditions. This process is mediated by prolyl hydroxylase domain proteins, the inhibition of which results in an increased expression of hypoxia-induced genes, including erythropoietin. These findings led to the development of prolyl hydroxylase domain inhibitors as novel therapeutic agents against anemia in chronic kidney disease. Prolyl hydroxylase domain inhibition improves iron metabolism, which also contributes to erythropoiesis. To date, at least 6 small-molecule inhibitors of the prolyl hydroxylase domain have been tested in humans, and clinical trials have shown that they are effective without causing serious adverse events. However, there is a theoretical concern that the systemic activation of HIF could also induce deleterious effects such as tumorigenesis and severe pulmonary hypertension, which demands careful assessments in future clinical studies.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Hypoxia-Inducible Factor 1; Iron; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).. To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.. Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.. We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life.. There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Cause of Death; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Middle Aged; Polyethylene Glycols; Publication Bias; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Thrombosis

Anaemia is a commonly diagnosed complication among patients suffering with chronic kidney disease. If left untreated, it may affect patient quality of life. There are several causes for anaemia in this patient population. As the kidney function deteriorates, together with medications and dietary restrictions, patients may develop iron deficiency, resulting in reduction of iron supply to the bone marrow (which is the body organ responsible for the production of different blood elements). Chronic kidney disease patients may not be able to utilise their own body's iron stores effectively and hence, many patients, particularly those receiving haemodialysis, may require additional iron treatment, usually provided by infusion.With further weakening of kidney function, patients with chronic kidney disease may need additional treatment with a substance called erythropoietin which drives the bone marrow to produce its own blood. This substance, which is naturally produced by the kidneys, becomes relatively deficient in patients with chronic kidney disease. Any patients will eventually require treatment with erythropoietin or similar products that are given by injection.Over the last few years, several iron and erythropoietin products have been licensed for treating anaemia in chronic kidney disease patients. In addition, several publications discussed the benefits of each treatment and possible risks associated with long term treatment. The current guidelines provide advice to health care professionals on how to screen chronic kidney disease patients for anaemia, which patients to investigate for other causes of anaemia, when and how to treat patients with different medications, how to ensure safe prescribing of treatment and how to diagnose and manage complications associated with anaemia and the drugs used for its treatment.

Topics: Anemia; Erythropoietin; Humans; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic

The benefits of erythropoiesis-stimulating agents (ESA) for chronic kidney disease (CKD) patients have been previously demonstrated. However, the efficacy and safety of short-acting epoetins administered at larger doses and reduced frequency as well as of new epoetins and biosimilars remains uncertain.. This review aimed to evaluate the benefits and harms of different routes, frequencies and doses of epoetins (epoetin alpha, epoetin beta and other short-acting epoetins) for anaemia in adults and children with CKD not receiving dialysis.. We searched the Cochrane Kidney and Transplant Specialised Register to 12 September 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised control trials (RCTs) comparing different frequencies, routes, doses and types of short-acting ESAs in CKD patients.. Two authors independently assessed study eligibility and four authors assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random-effects model.. We identified 14 RCTs (2616 participants); nine studies were multi-centre and two studies involved children. The risk of bias was high in most studies; only three studies demonstrated adequate random sequence generation and only two studies were at low risk of bias for allocation concealment. Blinding of participants and personnel was at low risk of bias in one study. Blinding of outcome assessment was judged at low risk in 13 studies as the outcome measures were reported as laboratory results and therefore unlikely to be influenced by blinding. Attrition bias was at low risk of bias in eight studies while selective reporting was at low risk in six included studies.Four interventions were compared: epoetin alpha or beta at different frequencies using the same total dose (six studies); epoetin alpha at the same frequency and different total doses (two studies); epoetin alpha administered intravenously versus subcutaneous administration (one study); epoetin alpha or beta versus other epoetins or biosimilars (five studies). One study compared both different frequencies of epoetin alpha at the same total dose and at the same frequency using different total doses.Data from only 7/14 studies could be included in our meta-analyses. There were no significant differences in final haemoglobin (Hb) levels when dosing every two weeks was compared with weekly dosing (4 studies, 785 participants: MD -0.20 g/dL, 95% CI -0.33 to -0.07), when four weekly dosing was compared with two weekly dosing (three studies, 671 participants: MD -0.16 g/dL, 95% CI -0.43 to 0.10) or when different total doses were administered at the same frequency (four weekly administration: one study, 144 participants: MD 0.17 g/dL 95% CI -0.19 to 0.53).Five studies evaluated different interventions. One study compared epoetin theta with epoetin alpha and found no significant differences in Hb levels (288 participants: MD -0.02 g/dL, 95% CI -0.25 to 0.21). One study found significantly higher pain scores with subcutaneous epoetin alpha compared with epoetin beta. Two studies (165 participants) compared epoetin delta with epoetin alpha, with no results available since the pharmaceutical company withdrew epoetin delta for commercial reasons. The fifth study comparing the biosimilar HX575 with epoetin alpha was stopped after patients receiving HX575 subcutaneously developed anti-epoetin antibodies and no results were available.Adverse events were poorly reported in all studies and did not differ signif. Epoetin alpha given at higher doses for extended intervals (two or four weekly) is non-inferior to more frequent dosing intervals in maintaining final Hb levels with no significant differences in adverse effects in non-dialysed CKD patients. However the data are of low methodological quality so that differences in efficacy and safety cannot be excluded. Further large, well designed, RCTs with patient-centred outcomes are required to assess the safety and efficacy of large doses of the shorter acting ESAs, including biosimilars of epoetin alpha, administered less frequently compared with more frequent administration of smaller doses in children and adults with CKD not on dialysis.

Topics: Adult; Anemia; Child; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobin A; Humans; Injections, Intravenous; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) is an important health problem, because of unsuccessful outcomes such as CKD progression to end stage renal disease and high risk of cardiovascular disease (CVD). Anemia, associated with CKD, is considered a non-traditional risk factor for CVD which may contribute to faster CKD progression. Anemia treatment with erythropoiesis-stimulating agents (ESAs) seems to exert non-hematopoietic effects on different tissues and organs, including cardiovascular system and kidneys. On the other hand, clinical use of high doses of short-acting ESAs and higher target hemoglobin level were associated with higher risk of CVD. Literature data indicate the usefulness of long-acting ESAs in treatment of anemia in non-dialysis CKD patients. In particular, continuous erythropoietin receptor activator seems to be a good choice in these patients because of its efficiency, safety and monthly administration. Continuous but slower erythropoietin receptor activation, using methoxy polyethylene glycol-epoetin beta (MPG-EPO), administered once a month, slowly corrects anemia without exceeding the recommended hemoglobin level. An overview of the available literature may suggest nephroprotective and cardiovascular protective effects of MPG-EPO. It seems possible that anemia treatment with a novel ESAs, MPG-EPO in early stages of CKD may reduce CVD risk in these patients and delay CKD progression. This review of available literature evaluates the correlation between continuous erythropoietin receptor activation using MPG-EPO and CKD progression and CVD risk in non-dialysis CKD patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematinics; Humans; Kidney; Polyethylene Glycols; Renal Insufficiency, Chronic; Risk Factors

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

Topics: Anemia; Barbiturates; Clinical Trials as Topic; Enzyme Inhibitors; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Pyrazoles; Renal Insufficiency, Chronic; Triazoles

Anemia is a common complication in patients with chronic kidney disease (CKD), mainly due to inadequate renal production of erythropoietin. In hemodialysis (HD) patients this condition may be aggravated by iron deficiency (absolute or functional). The correction of this anemia is usually achieved by treatment with erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies questioning the safety of ESAs (especially at higher doses) changed the pattern of anemia treatment in CKD patients. According to the new guidelines, when transferrin saturation is lower than 30% and ferritin lower than 500 ng/mL, a trial with iron should be started, to avoid therapy with ESAs or at least to reduce the doses needed to treat the anemia. Recent reports showed increasing ferritin levels, towards values above 800 ng/mL, in CKD patients treated according to the guidelines. In this review we focus on the risks of the increased iron use to treat CKD anemia, namely, iron overload and toxicity, increased risk of infections, as well as mortality.

Topics: Anemia, Iron-Deficiency; Drug Dosage Calculations; Epoetin Alfa; Erythropoietin; Ferritins; Hematinics; Humans; Iron; Iron Overload; Kidney; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Survival Analysis; Transferrin

Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.

Topics: Anemia; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) anemia treatment was revolutionized in the late 1980s with the introduction of recombinant human erythropoietin. This and related erythropoiesis-stimulating agents (ESAs) greatly benefited patients by decreasing debilitating symptoms, improving their quality of life, and freeing them from dependence on blood transfusions with their associated complications such as infections, sensitization impeding transplantation, and secondary iron overload. However, even in the initial studies, untoward effects were noted in patients receiving ESAs, including worsening hypertension, seizures, and dialysis access clotting. Later, increased mortality, malignancy progression and even stroke were reported in renal patients. This review focuses on the safety issues of ESAs in CKD patients.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs.. By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed.. Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated.

Topics: Anemia; Animals; Biological Products; Drug Design; Drug Resistance; Drugs, Investigational; Erythropoietin; Hematinics; Humans; Peptides; Renal Insufficiency, Chronic

Erythropoiesis stimulating agents (ESA) are effective drugs, which have been used for decades in patients with chronic kidney disease (CKD) with few side effects. More recently, concern has been raised around their safety, from higher cardiovascular and thrombosis risk to cancer progression and increased mortality.. We made a literature search on PubMed looking for adverse effects of ESA in CKD patients. The topics covered are cardiovascular adverse events, thrombosis, increased mortality, hypertension, cancer progression, diabetic retinopathy, pure red cell aplasia and anaphylactic reactions.. Concerns around ESA therapy have questioned treatment indications in high-risk CKD patients (those with cancer, diabetes and cardiovascular comorbidities). A more cautious approach has then prevailed. In our opinion, intermediate Hb values (Hb 10-12 g/dl) should be aimed with ESA therapy, being more cautious in high-risk patients. As a consequence, IV iron is administered more frequently. However, excessive iron use may cause iron overload and in rare cases severe anaphylactic reactions. There are expectations of new erythropoietic agents, such as those manipulating the hypoxia-inducible transcription factors (HIF) system. Differing from ESAs, they stimulate the production of endogenous EPO, avoiding over-physiological plasmatic levels.

Topics: Anemia; Animals; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Renal Insufficiency, Chronic; Risk Factors

Anemia of renal disease is common and is associated with significant morbidity and death. It is mainly caused by a decrease in erythropoietin production in the kidneys and can be partially corrected with erythropoiesis-stimulating agents (ESAs). However, randomized controlled trials have shown that using ESAs to target normal hemoglobin levels can be harmful, and have called into question any benefits of ESA treatment other than avoidance of transfusions.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney; Renal Insufficiency, Chronic

Backgroud. Anemia is one of the laboratory and clinical findings of chronic kidney diseases (CKD). The presence of anemia in patients with CKD has a wide range of clinically important consequences. Some of the symptoms that were previously attributed to reduced renal function are, in fact, a consequence of anemia. Anemia contributes to increased cardiac output, the development of left ventricular hypertrophy, angina, and congestive heart failure. According to current knowledge, anemia also contributes to the progression of CKD and is one of the factors that contribute to the high morbidity and mortality in patients with chronic renal failure and their reduced survival.. MEDLINE search was performed to collect both original and review articles addressing anemia in CKD, pathophysiology of renal anemia, erythropoiesis, erythropoietin, iron metabolism, inflammation, malnutrition, drugs, renal replacement therapy and anemia management. The present review summarized current knowledge in the field of the pathophysiology of renel anemia. Understanding the pathophysiology of anemia in CKD is crucial for the optimal treatment of anemia according to recent clinical practice guidelines and recommendation, and correct recognition of causes of resistence to treatment of erythropoietin stimulating agents (ESA).

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron Deficiencies; Iron Metabolism Disorders; Renal Insufficiency, Chronic

The management of anemia in patients with chronic kidney disease (CKD) is difficult. The availability of erythropoiesis-stimulating agents (ESAs) has increased treatment options for previously transfusion-requiring patients, but the recent evidence of ESA side effects has prompted the search for complementary or alternative approaches. Next to ESA, parenteral iron supplementation is the second main form of anemia treatment. However, as of now, no systematic approach has been proposed to balance the concurrent administration of both agents according to individual patient's needs. Furthermore, the potential risks of excessive iron dosing remain a topic of controversy. How, when and whether to monitor CKD patients for potential iron overload remain to be elucidated. This review addresses the question of risk and benefit of iron administration in CKD, highlights the evidence supporting current practice, provides an overview of standard and potential new markers of iron status and outlines a new pharmacometric approach to physiologically compatible individualized dosing of ESA and iron in CKD patients.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Hematinics; Humans; Iron Compounds; Iron Overload; Renal Insufficiency, Chronic

Renal fibrosis is a major hallmark of chronic kidney disease that is considered to be a common end point of various types of renal disease. To date, the biological meaning of fibrosis during the progression of chronic kidney diseases is unknown and possibly depends on the cell type contributing to extracellular matrix production. During the past decade, the origin of myofibroblasts in the kidney has been intensively investigated. Determining the origins of renal myofibroblasts is important because these might account for the heterogeneous characteristics and behaviors of myofibroblasts. Current data strongly suggest that collagen-producing myofibroblasts in the kidney can be derived from various cellular sources. Resident renal fibroblasts and cells of hematopoietic origin migrating into the kidney seem to be the most important ancestors of myofibroblasts. It is likely that both cell types communicate with each other and also with other cell types in the kidney. In this review, we will discuss the current knowledge on the origin of scar-producing myofibroblasts and cellular events triggering fibrosis.

Topics: Actins; Anemia; Animals; Cell Movement; Disease Progression; Epithelial-Mesenchymal Transition; Erythropoietin; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Kidney; Models, Biological; Myofibroblasts; Pericytes; Renal Insufficiency, Chronic

Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with advanced chronic kidney disease and end-stage renal disease. No study has specifically compared the risks of hard study outcomes between EPO and DPO, including mortality.. Systematic review of the literature and meta-analysis.. Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis.. We conducted a systematic search of the literature (PubMed, CENTRAL, SCOPUS, and EMBASE, all years) and industry resources, using predefined search terms and data abstraction tools. We then summarized key characteristics and findings of these trials and performed a random-effects meta-analysis of trials with at least 3 months' duration to identify the summary OR of mortality between patients randomly assigned to DPO versus EPO.. DPO versus EPO.. All-cause mortality.. We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic=4.60; P=0.8).. Generalizability to nontrial populations is uncertain.. Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO. Absent adequately powered randomized trials, observational postmarketing comparative effectiveness studies comparing these erythropoiesis-stimulating agents are required to better characterize the long-term safety profiles of these agents.

Topics: Anemia; Cause of Death; Darbepoetin alfa; Double-Blind Method; Epoetin Alfa; Erythropoietin; Half-Life; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

The association between chronic kidney disease (CKD) and cardiovascular disease (CVD) is well established, and there is mounting evidence of interorgan cross talk that may accelerate pathologic processes and the progression of organ dysfunction in both systems. This process, termed cardiorenal syndrome (CRS) by the Acute Dialysis Quality Initiative, is considered a major health problem: patients with CKD and CVD are at much higher risk of mortality than patients with either condition alone. To date, the majority of CRS research has focused on neurohormonal mechanisms and hemodynamic alterations. However, mounting evidence suggests that abnormalities in the normal pathophysiology of the bone-mineral axis, iron, and erythropoietin play a role in accelerating CKD and CVD. The goal of this article is to review the role and interrelated effects of the bone-mineral axis and anemia in the pathogenesis of chronic CRS.

Topics: Anemia; Bone and Bones; Calcifediol; Calcitriol; Calcium; Cardio-Renal Syndrome; Cardiovascular Diseases; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Iron; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic

Topics: Anemia; Disease Management; Drug Administration Routes; Erythropoietin; Humans; Iron; Iron Deficiencies; Renal Insufficiency, Chronic; Severity of Illness Index; Trace Elements

The European Medicines Agency (EMA), under a strictly regulated pathway, has approved several biosimilar products since 2005, including biosimilar versions of the erythropoiesis-stimulating agent (ESA) epoetin alfa since 2007. Subsequent to these approvals, the use of biosimilar epoetin alfa in the management of renal anemia has grown steadily throughout Europe. With the enactment of the US Biologics Price Competition and Innovation Act of 2009, a US Food and Drug Administration regulatory approval process for biosimilars was legalized. Thus, biosimilar erythropoietin products are expected to be available for prescription in the USA by mid-decade, presumably at a price that is competitive with the originator brand-name reference products. In this paper, we describe the status of originator and biosimilar ESAs, review the clinical development and regulatory approval of biosimilar erythropoietins in Europe, and summarize relevant efficacy and safety information of biosimilar erythropoietins in relation to their reference products to provide a background for US nephrologists as they appraise biosimilar erythropoietins as treatment options for renal anemia. Key lessons learned from Europe are that (a) EMA-approved biosimilar erythropoietins have comparable efficacy and safety profiles to their reference product erythropoietin; (b) pharmacovigilance preapproval and postapproval are critical, especially with regard to immunogenicity and vascular thromboembolic events; (c) strict preapproval and postapproval requirements must guide the regulatory pathway for biosimilars; and (d) high-quality manufacturing and production processes must be established to ensure quality biosimilar products. The availability of biosimilar erythropoietins in the USA will provide nephrologists with alternative effective, and potentially more affordable, treatment options for patients with renal anemia.

Topics: Anemia; Biosimilar Pharmaceuticals; Disease Management; Erythropoietin; Europe; Humans; Renal Insufficiency, Chronic; United States

Renal anemia is caused by the deficiency of endogenous erythropoietin (Epo) due to renal dysfunction. We think that it is possible to slow the progression of chronic kidney disease (CKD) in case we initiate Epo early in pre-dialysis patients, especially in the non-diabetic population. Erythropoiesis stimulating agent (ESA) treatments targeting mild anemia (10-12 g/dl) can decrease the risk of occurrence of cardiovascular disease (CVD) in patients with hypertension, diabetes mellitus and congestive heart failure. As the large randomized controlled trials such as Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency and Trial to Reduce Cardiovascular Events with Aranesp Thearpy in the Western countries suggested, we do not recommend high doses of ESA to achieve the target hemoglobin (Hb) level. The target Hb of >13 g/dl might lead to increase in the risk of CVD although maintaining a high Hb of >12 g/dl without ESA is not harmful for CKD patients. It is desirable to determine the target Hb in dialysis patients depending on their ages. Renal anemia should be monitored constantly to start ESA and iron replacement therapy at an appropriate time, while avoiding their excess in order to minimize the occurrence of CVD and other complications. Taken all the international guidelines and our clinical experiences together, we should consider administration of ESA when the Hb level becomes <11 g/dl in pre-dialysis patients and <10 g/dl in dialysis patients.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietin-stimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy.

Topics: Anemia; Contraindications; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Receptors, Erythropoietin; Renal Insufficiency, Chronic; Risk Factors

Erythropoiesis-stimulating agents are used to treat anaemia in people with chronic kidney disease (CKD). Several agents are available including epoetin alfa or beta as well as agents with a longer duration of action, darbepoetin alfa and methoxy polyethylene glycol-epoetin beta.. To assess the benefits and harms of darbepoetin alfa to treat anaemia in adults and children with CKD (stages 3 to 5, 5D, and kidney transplant recipients).. We searched the Cochrane Renal Group's Specialised Register (to 13 January 2014) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE.. We included randomised controlled trials of any darbepoetin alfa treatment of at least three months duration in adults or children with CKD (any stage).. Data were extracted by two independent investigators. Patient-centred outcomes (need for blood transfusion, iron therapy, progression of kidney disease, total and cardiovascular mortality, cardiovascular events, cancer, hypertension, seizures, and health-related quality of life) and other outcomes (haemoglobin levels) were assessed using random effects meta-analysis. We calculated risk ratios for dichotomous outcomes and mean differences for continuous outcomes, both with 95% confidence intervals.. We identified 32 studies comprising 9414 participants; 21 studies in 8328 participants could be included in our meta-analyses. One study (4038 participants) compared darbepoetin alfa to placebo, 16 studies (2955 participants) compared darbepoetin alfa to epoetin alfa or beta, four studies (1198 participants) compared darbepoetin alfa to methoxy polyethylene glycol-epoetin beta, three studies (420 participants) compared more frequent with less frequent darbepoetin alfa administration and four studies (303 participants) compared intravenous with subcutaneous darbepoetin alfa administration.In a single large study, darbepoetin alfa reduced the need for blood transfusion and iron therapy compared with placebo in adults with CKD stage 3 to 5, but had little or no effect on survival, increased risks of hypertension, and had uncertain effects on quality of life. Data comparing darbepoetin alfa with epoetin alfa or beta or methoxy polyethylene glycol-epoetin beta were sparse and inconclusive. Comparisons of differing dosing schedules and routes of administration were compared in small numbers of participants and studies. Evidence for treatment effects of darbepoetin alfa were particularly limited for children with CKD, adults with CKD stage 5D, and recipients of a kidney transplant.Studies included in this review were generally at high or unclear risk of bias for all items (random sequence generation, allocation concealment, incomplete outcome data, blinding of participants and personnel, blinding of outcome assessment, selective outcome reporting, intention to treat analysis and other sources of bias). One large study comparing darbepoetin alfa with placebo was at low risk of bias for most items assessed.. Data suggest that darbepoetin alfa effectively reduces need for blood transfusions in adults with CKD stage 3 to 5, but has little or no effect on mortality or quality of life. The effects of darbepoetin alfa in adults with CKD stage 5D and kidney transplant recipients and children with CKD remain uncertain as do the relative benefits and harms of darbepoetin alfa compared with other ESAs (epoetin alfa or beta and methoxy polyethylene glycol-epoetin beta).

Topics: Adult; Anemia; Child; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Transplantation; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

Chronic Kidney Disease (CKD) has adverse consequences on almost all body systems. The kidney does not function merely as an excretory organ, but participates in normal erythropoiesis, normal bone mineral deposition and blood pressure regulation.. Anemia is prevalent in CKD with known deleterious effects on the car diovascular system. It is mostly due to erythropoietin deficiency, inhibition of erythropoiesis by uremic solutes, and reduction in red blood cell life span. Other possible causes include iron, B12 or folic acid deficiency or blood loss. Dysfunction of the endogenous erythropoietin is usually clinically evident once the glomerular filtration rate (GFR) falls below 20-25 ml/min. Treating anemia of CKD is based on correction of iron deficiency and replacement of decreased erythropoietin production by erythropoietin stimulating agents (ESA). Guidelines recommend targeting hemoglobin levels of no more than 10-12 g/dl since there is evidence of increased mortality and morbidity in patients with higher levels. Increased level of pro-coagulant biomarkers cause enhanced thrombotic activity in CKD patients which promotes ischemic cardiac events while platelet dysfunction leads to bleeding diathesis. If anticoagulation is indicated, low molecular weight heparins (LMWHs) offer certain advantage sbut the dosage needs to be adjusted with increasing grade of renal insufficiency. Antiplatelet agents are effective in averting shunt and catheter thrombosis, but not for avoiding the thrombosis of arteriovenous grafts.. Health related quality of life in CKD patients can be improved by treating anemia. Newly available ESAs and the entry into the market of epoetinbiosimilars are expected to lead to improvements in the management of CKD and its complications.

Topics: Anemia; Erythropoiesis; Erythropoietin; Glomerular Filtration Rate; Hematinics; Humans; Quality of Life; Renal Insufficiency, Chronic

Renal pericytes have been neglected for many years, but recently they have become an intensively studied cell population in renal biology and pathophysiology. Pericytes are stromal cells that support vasculature, and a subset of pericytes are mesenchymal stem cells. In kidney, pericytes have been reported to play critical roles in angiogenesis, regulation of renal medullary and cortical blood flow, and serve as progenitors of interstitial myofibroblasts in renal fibrogenesis. They interact with endothelial cells through distinct signaling pathways and their activation and detachment from capillaries after acute or chronic kidney injury may be critical for driving chronic kidney disease progression. By contrast, during kidney homeostasis it is likely that pericytes serve as a local stem cell population that replenishes differentiated interstitial and vascular cells lost during aging. This review describes both the regenerative properties of pericytes as well as involvement in pathophysiologic conditions such as fibrogenesis.

Topics: Acute Kidney Injury; Erythropoietin; Fibrosis; Humans; Kidney; Mesenchymal Stem Cells; Neovascularization, Physiologic; Pericytes; Regeneration; Renal Insufficiency, Chronic

Anemia management in non-dialysis-dependent chronic kidney disease (CKD) patients is associated with cardiovascular and cost benefits, slows decline in renal function, and prevents mortality. Different reviews have focused on evaluating the safety and efficacy of methoxy polyethylene glycol-epoetin beta (MPG-EPO), a continuous erythropoietin receptor activator, in CKD patients regardless of dialysis dependency and others have studied this novel agent exclusively in CKD patients receiving dialysis.. To evaluate the efficacy and tolerability of MPG-EPO compared with other erythropoiesis stimulating agents (in particular darbepoetin alfa) for the treatment of anemia in non-dialysis-dependent CKD patients.. A systematic review of original studies published mainly in MEDLINE, Cochrane Database, ScienceDirect, ProQuest, clinical trials registries, and Google Scholar was carried out to identify randomized controlled trials (RCTs) comparing MPG-EPO with other erythropoiesis stimulating agents or placebo among patients with anemia of CKD who were not yet receiving dialysis. Data were independently extracted by two reviewers using standardized data abstraction tool.. Four trials involving 1,155 patients were included in the review. The changes in hemoglobin level from the baseline reported by the reviewed studies demonstrate that MPG-EPO was clinically non-inferior to darbepoetin alfa. In addition, the studies documented that MPG-EPO-treated patients experienced a lower rate of hemoglobin level above the target range of 12-13 g/dL than darbepoetin-treated patients. The proportion of patients requiring RBC transfusion was higher among patients who received darbepoetin alfa than those who received MPG-EPO. However, the time to hemoglobin response was longer with MPG-EPO than with darbepoetin. Finally, the incidences of serious adverse events were similar between the two therapeutic agents.. There are currently only few well-designed head-to-head RCTs investigating the efficacy and safety of MPG-EPO compared with other ESAs in non-dialysis-dependent patients. MPG-EPO therapy compared with darbepoetin alfa has demonstrated favorable effects of increasing and maintaining hemoglobin concentrations to recommended target levels. This mini-review is not conclusive due to limited number of studies. Therefore, the beneficial effects and tolerability of MPG-EPO among non-dialysis-dependent CKD patients should be further investigated, given the economic and clinical benefits of managing anemia in this population.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Anaemia occurs when blood contains fewer red blood cells and lower haemoglobin levels than normal, and is a common complication among adults with chronic kidney disease (CKD). Although a number of approaches are applied to correct anaemia in adults with CKD, the use of androgen therapy is controversial.. The aim of this review was to determine the benefits and harms of androgens for the treatment of anaemia in adult patients with CKD.. We searched CENTRAL, the Cochrane Renal Group's Specialised Register, the Chinese Biomedicine Database (CBM), CNKI, VIP and reference lists of articles without language restriction. The most recent search was conducted in August 2014.. All randomised controlled trials (RCTs) that assessed the use of androgens for treating anaemia of CKD in adults were eligible for inclusion.. Two authors independently extracted data and assessed risk of bias in the included studies. Meta-analyses were performed using relative risk (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).. We included eight studies that reported data from 181 participants. Study quality was assessed as moderate in six studies, one was low quality, and one was high quality. The small number of included studies, and low participant numbers adversely influenced evidence quality overall.We found limited evidence (1 study, 24 participants) to indicate that oxymetholone can increase haemoglobin (Hb) (MD 1.90 g/dL, 95% CI 1.66 to 2.14), haematocrit (HCT) (MD 27.10%, 95% CI 26.49 to 27.71), change in albumin (MD 4.91 g/L, 95% CI 3.69 to 6.13), alanine aminotransferase (ALT) (MD 54.50 U/L, 95% CI 43.94 to 65.06), and aspartate aminotransferase (AST) (MD 47.33 U/L, 95% CI 37.69 to 56.97); and decrease high-density lipoprotein (HDL) (MD -15.66 mg/dL, 95% CI -24.84 to -6.48). We also found that compared with erythropoietin alone, nandrolone decanoate plus erythropoietin may increase HCT (3 studies, 73 participants: MD 2.54%, 95% Cl 0.96 to 4.12). Compared with erythropoietin (1 study, 27 participants), limited evidence was found to suggest that nandrolone decanoate can increase plasma total protein (MD 0.40 g/L, 95% CI 0.13 to 0.67), albumin (MD 0.20 g/L, 95% CI 0.01 to 0.39), and transferrin (MD 45.00 mg/dL, 95% CI 12.61 to 77.39) levels. Compared with no therapy (remnant kidney), evidence was found to suggest that nandrolone decanoate can increase Hb (2 studies, 33 participants: MD 1.04 g/dL, 95% Cl 0.66 to 1.41) and HCT (1 study, 24 participants: MD 3.70%, 95% Cl 0.68 to 6.72). Compared with no therapy (anephric), evidence was found (1 study, 5 participants) to suggest that nandrolone decanoate can increase Hb (MD 1.30 g/dL, 95% Cl 0.57 to 2.03), but nandrolone decanoate did not increase HCT (MD 2.00%, 95% Cl -0.85 to 4.85).However, oxymetholone was not found to reduce blood urea nitrogen (BUN), serum creatinine (SCr), cholesterol, or triglycerides; or increase plasma total protein, prealbumin, or transferrin. No evidence was found to indicate that nandrolone decanoate increased prealbumin or decreased BUN, SCr, AST, ALT, cholesterol, triglycerides, HDL or low-density lipoprotein (LDL). Adverse events associated with androgen therapy were reported infrequently.. We found insufficient evidence to confirm that use of androgens for adults with CKD-related anaemia is beneficial.

Topics: Adult; Androgens; Anemia; Cholesterol; Erythropoietin; Hematocrit; Humans; Nandrolone; Nandrolone Decanoate; Oxymetholone; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Triglycerides

There is a well-documented association between erythropoiesis-stimulating agents (ESAs) and hypertension in chronic kidney disease. Studies suggest that the mechanism for this is multifactorial. First, some chronic kidney disease patients may have a limited ability to accommodate a rapid increase in red cell volume because of a decreased glomerular filtration rate, left ventricular hypertrophy, and decreased arterial compliance. Second, there is likely a direct vasoconstrictor effect of ESAs. Although no large randomized controlled trials of ESAs have been designed with blood pressure as an a priori outcome, several meta-analyses have explored this relationship and generally support the existence of ESA-induced hypertension. There are as of yet no data directly linking ESA-induced hypertension with increased cardiovascular morbidity and mortality. Despite this, clinicians should be vigilant for ESA-induced hypertension, use caution when using ESAs in patients with resistant hypertension, and be attentive to the rate of hemoglobin increase in patients with poorly controlled blood pressure.

Topics: Anemia; Blood Pressure; Drug Resistance; Endothelin-1; Erythropoietin; Hematinics; Humans; Hypertension; Nitric Oxide; Recombinant Proteins; Renal Insufficiency, Chronic; Renin-Angiotensin System

Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies.. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD.. We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion.. Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high.. We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses.. In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Polyethylene Glycols; Recombinant Proteins; Renal Insufficiency, Chronic

Anemia in chronic kidney disease (CKD) may affect up to 90% of the patients. It is one of the non typical risk factors of cardiovascular disease, specific for this population. The main reasons of the anemia in CKD are iron and erythropoietin deficiency. It is recognized in women with hemoglobin concentration < 11 g/dl and in men and postmenopausal women with hemoglobin concentration < 12 g/dl. Other potentially reversible reasons of anemia should be excluded in differential diagnosis. Iron and erythropoiesis stimulating agents (ESA) constitute the main treatment of anemia of CKD.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Causality; Comorbidity; Erythropoietin; Female; Hematinics; Humans; Male; Renal Insufficiency, Chronic; Risk Factors

Anemia is a frequent comorbidity of heart failure and is associated with poor outcomes. Anemia in heart failure is considered to develop due to a complex interaction of iron deficiency, kidney disease, and cytokine production, although micronutrient insufficiency and blood loss may contribute. Currently, treatment of anemia of heart failure lacks clear targets and specific therapy is not defined. Intravenous iron use has been shown to benefit anemic as well as nonanemic patients with heart failure. Treatment with erythropoietin-stimulating agents has been considered alone or in combination with iron, but robust evidence to dictate clear guidelines is not currently available. Available and emerging new agents in the treatment of anemia of heart failure will need to be tested in randomized, controlled studies.

Topics: Age Factors; Aged; Anemia; Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Incidence; Inflammation Mediators; Iron; Male; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sex Factors

Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.

Topics: Anemia; Animals; Cytokines; Erythropoietin; Humans; Inflammation; Renal Insufficiency, Chronic; Vitamin D Deficiency

Topics: Animals; Epoetin Alfa; Erythropoietin; Fibrosis; Hematinics; Humans; Kidney; Recombinant Proteins; Renal Insufficiency, Chronic

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases, with an increasing rate in morbidity and mortality. In recent years, there has been a greater awareness about the clinical importance of systemic effects and other chronic conditions associated with COPD, as these significantly impact on the course of disease. The most studied extrapulmonary manifestations in COPD include the presence of concomitant cardiovascular disease, skeletal muscle wasting, osteoporosis and lung cancer. Anaemia is a recognised independent marker of mortality in several chronic diseases. Recent studies have shown that anaemia in patients with COPD may be more frequent than expected, with a prevalence ranging from 5% to 33%. Some evidence suggests that systemic inflammation may play an important pathogenic role, but anaemia in COPD is probably multifactorial and may be caused by others factors, such as concealed chronic renal failure, decreased androgenic levels, iron depletion, angiotensin-converting enzyme inhibitor treatment and exacerbations. Low levels of haemoglobin and haematocrit in COPD patients have been associated with poor clinical and functional outcomes as well as with mortality and increased healthcare costs. Despite the potential clinical benefit of successfully treating anaemia in these patients, evidence supporting the importance of its correction on the prognosis of COPD is uncertain.

Topics: Acute Disease; Androgens; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Exercise Tolerance; Glomerular Filtration Rate; Health Resources; Hemoglobins; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Renal Insufficiency, Chronic; Renin-Angiotensin System

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron; Recombinant Proteins; Renal Insufficiency, Chronic

Renal anemia has been recognized as a characteristic complication of chronic kidney disease. Although many factors are involved in renal anemia, the predominant cause of renal anemia is a relative deficiency in erythropoietin (EPO) production. To date, exogenous recombinant human (rh)EPO has been widely used as a powerful drug for the treatment of patients with renal anemia. Despite its clinical effectiveness, a potential risk for increased mortality has been suggested in patients who receive rhEPO, in addition to the economic burden of rhEPO administration. The induction of endogenous EPO is another therapeutic approach that might have advantages over rhEPO administration. However, the physiological and pathophysiological regulation of EPO are not fully understood, and this lack of understanding has hindered the development of an endogenous EPO inducer. In this review, we will discuss the current treatment for renal anemia and its drawbacks, provide an overview of EPO regulation in healthy and diseased conditions, and propose future directions for therapeutic trials that more directly target the underlying pathophysiology of renal anemia.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) prevent transfusions among anemic patients with chronic kidney disease (CKD). Clinical trials, meta-analyses, and guidelines identify arterial and venous thromboembolism as well as myocardial event risks with the traditional ESAs, erythropoietin (EPO), and darbepoietin. Side effects of anemia treatment, considering frequency and dosage of treatment as well as targeted hemoglobin levels when utilizing ESAs, greatly impact overall well-being and the quality of life. There is a need for less frequent but equally effective ESAs in this setting.. The three generations of ESAs used in CKD-associated anemia are described. Cost effectiveness of the utilization of these therapies, in addition to emerging therapies, is also presented. The few clinical and controlled trials only highlight the need for clarity in molecular biology surrounding the components that control EPO levels and utilization.. Anemia associated with CKD is an important area for development of newer therapies which are potentially safer and more convenient to administer.

Topics: Anemia; Darbepoetin alfa; Drug Discovery; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Quality of Life; Recombinant Proteins; Renal Insufficiency, Chronic

Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.. Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level.. Patients with anemia of CKD irrespective of dialysis status.. We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.. ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.. All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement.. 31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events.. Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders.. In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.

Topics: Aged; Anemia; Cardiovascular Diseases; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Renal Insufficiency, Chronic; Risk Factors; Treatment Outcome

Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients.

Topics: Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Peptides; Polyethylene Glycols; Randomized Controlled Trials as Topic; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Topics: Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immune Tolerance; Protein Multimerization; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

It is known that the immunogenicity of hepatitis B virus (HBV) vaccine is lower in uremic patients than healthy subjects. Numerous inherited or acquired factors have been implicated in this lowered response, and the high frequency of recombinant human erythropoietin use among patients on maintenance dialysis has been suggested to play a pivotal role. However, the impact of therapy with recombinant erythropoietin on the immune response to HBV vaccine in patients with chronic kidney disease (CKD) is not appropriately detailed.. To evaluate the influence of human recombinant erythropoietin therapy on the immunological response to HBV vaccine in CKD patients by performing a systematic review of the literature with a meta-analysis of clinical studies.. We used the random-effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end-point of interest was the rate of patients showing seroprotective anti-hepatitis B titers at completion of a hepatitis B vaccine schedule among human erythropoietin users versus those who did not receive the drug in a CKD population.. We identified 11 studies involving 862 unique patients with CKD. Aggregation of study results did not show a significant increase in response rates among erythropoietin user versus non-user patients (pooled odds ratio = 1.431; 95% CI 0.954; 2.146), according to a random-effects model. No heterogeneity was found, the p value was 0.1 for our test of study heterogeneity (Q = 14.147). Stratified analysis in various subgroups of interest did not significantly change these findings.. Our meta-analysis showed no link between immunological response to HBV vaccine and therapy with human recombinant erythropoietin among individuals on long-term dialysis. We suggest the use of recombinant vaccine towards hepatitis B in patients on regular dialysis irrespective of erythropoietin treatment.

Topics: Erythropoietin; Hepatitis B Vaccines; Humans; Immunogenetic Phenomena; Renal Insufficiency, Chronic

Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.

Topics: Anemia; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Erythropoiesis; Erythropoietin; Hepcidins; Homeostasis; Humans; Iron, Dietary; Models, Biological; Renal Insufficiency, Chronic

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk-benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

Topics: Darbepoetin alfa; Erythropoietin; Humans; Neoplasms; Peptides; Renal Insufficiency, Chronic

Interpretation of the results of earlier meta-analyses in chronic kidney disease (CKD) patients on the impact of anaemia treatment with erythropoiesis-stimulating agents (ESAs) on clinical outcomes has been hampered by the inclusion of small trials and trials of short duration. We re-evaluated the benefits and harms of treating anaemia, including only relevant clinical trials.. We conducted a systematic review and meta-analysis of randomised controlled trials performed in adults with CKD which allocated patients to different doses of ESAs, and we compared the effect of these interventions on vascular access thrombosis, stroke, risk of end-stage renal disease (ESRD) and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants.. Five trials (7,902 participants) met the inclusion criteria and were included in the meta-analysis. The number of patients enrolled in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. A higher haemoglobin target was associated with increased risk of vascular access thrombosis (RR 1.343; 95% CI 1.162-1.554; p = 0.0005) and stroke (RR 1.735; 95% CI 1.323-2.275; p = 0.0005), and no effect on risk of ESRD (RR 1.089; 95% CI 0.986-1.203; p = 0.094) or all-cause mortality (RR 1.148; 95% CI 0.977-1.350; p = 0.093).. In CKD patients, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk.

Topics: Adult; Anemia; Cardiovascular Diseases; Comorbidity; Erythropoietin; Hematinics; Humans; Incidence; Renal Insufficiency, Chronic; Risk Factors; Survival Analysis; Survival Rate; Treatment Outcome

Anemia is common in Congestive Heart Failure (CHF) and is associated with an increased mortality, morbidity and progressive renal failure. The most common causes of the anemia in CHF are (1) the associated Chronic Kidney Disease (CKD), which causes depression of erythropoietin (EPO) production in the kidney, and (2) excessive cytokine production in CHF, which can cause both depression of erythropoietin production in the kidney and depression of erythropoietin response in the bone marrow. The cytokines can also induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. It appears that iron deficiency is very common in CHF and is rarely recognized or treated. The iron deficiency can cause a thrombocytosis that might contribute to cardiovascular complications in both CHF and CKD and is reversible with iron treatment. Thus, attempts to control this anemia in CHF will have to take into consideration both the use of both Erythropoiesis Stimulating Agents (ESA) such as EPO and oral and, probably more importantly, intravenous (IV) iron. Many studies of anemia in CHF with ESA and oral or IV iron and even with IV iron without ESA have shown a positive effect on hospitalization, New York Heart Association functional class, cardiac and renal function, quality of life, exercise capacity and reduced Beta Natriuretic Peptide and have not demonstrated an increase in cardiovascular damage related to the therapy. However, adequately powered long-term placebo-controlled studies of ESA and of IV iron in CHF are still needed and are currently being carried out.

Topics: Anemia; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Erythropoietin; Heart Failure; Hematinics; Humans; Infusions, Intravenous; Iron; Iron Deficiencies; Kidney; Outcome Assessment, Health Care; Renal Insufficiency, Chronic; Syndrome; Trace Elements

Anemia is a common comorbidity in children with chronic kidney disease (CKD). This condition is associated with multiple adverse clinical consequences and its management is a core component of nephrology care. Increased morbidity and mortality, increased risk of cardiovascular disease and decreased quality of life have been associated with anemia of CKD in children. Although numerous complex factors interact in the development of this anemia, erythropoietin deficiency and iron dysregulation (including iron deficiency and iron-restricted erythropoiesis) are the primary causes. In addition to iron supplementation, erythropoietin-stimulating agents (ESAs) can effectively treat this anemia, but there are important differences in ESA dose requirements between children and adults. Also, hyporesponsiveness to ESA therapy is a common problem in children with CKD. Although escalating ESA doses to target increased hemoglobin values in adults has been associated with adverse outcomes, no studies have demonstrated this association in children. The question of appropriate target hemoglobin levels in children, and the approach by which to achieve these levels, remains under debate. Randomized, controlled studies are needed to evaluate whether normalization of hemoglobin concentrations is beneficial to children, and whether this practice is associated with increased risks.

Topics: Anemia; Child; Comorbidity; Erythropoietin; Humans; Renal Insufficiency, Chronic; Risk Factors

Erythropoiesis stimulating agents (ESAs) are effective drugs that correct anemia in patients with chronic kidney disease (CKD). Recombinant human erythropoietin (EPO), the first ESA that became available more than 20 years ago, is similar to the naturally occurring molecule. In subsequent years, pharmacological research focused on the development of new agents with improved characteristics, with the creation of high molecular weight ESAs having been the first approach. In more recent years, new agents have been developed, including peginesatide (Hematide; Affymax Inc/Takeda Pharmaceutical Co Ltd), which is a dimeric peptide with a chemical structure unrelated to EPO that is being evaluated in phase III clinical trials. In addition, the clinical development of two inhibitors of hypoxia-inducible transcription factor has been resumed recently, while other approaches, such as gene therapy and EPO fusion proteins, and the inhibition of GATA and hematopoietic cell phosphatase remain far from being applicable in clinical practice. New iron compounds, which are becoming increasingly available, will facilitate an integrated approach to anemia management using both iron and/or ESAs, according to the clinical needs of patients. This review discusses new therapeutic options (already available or still under development) for the treatment of CKD-associated anemia, including ESAs and intravenous iron molecules.

Topics: Anemia; Erythropoietin; Gene Expression Regulation; Genetic Therapy; Hematinics; Humans; Iron Compounds; Kidney; Kidney Failure, Chronic; Peptides; Recombinant Proteins; Renal Insufficiency, Chronic

End-stage renal disease (ESRD) affects more than 1500 people per million population in countries with a high prevalence, such as Japan, Taiwan, and the US. Approximately two-thirds of people with ESRD receive haemodialysis, one quarter have kidney transplants, and one tenth receive peritoneal dialysis.. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, erythropoietin, haemodialysis (standard-dose, increased-dose), high membrane-flux haemodialysis, increased-dose peritoneal dialysis, low membrane-flux haemodialysis, mupirocin, sevelamer, standard-dose dialysis, and statins.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic

It has recently been recognized that many patients with congestive heart failure (CHF) are anemic. The anemia is very often associated with chronic kidney disease (CKD). The more severe the anemia the more severe the CHF, with higher mortality, morbidity, and hospitalization rate. The only way to prove that the anemia is itself a causative factor in the progression of both the CKD and the CHF is to correct it. In this paper we review the results of published papers and some preliminary reports about correction of this anemia in CHF. These studies frequently showed that erythropoietic stimulating agents (ESA) with oral or IV iron often resulted in improvement in left ventricular systolic and diastolic function, dilation, and hypertrophy, stabilization or improvement in renal function, reduced hospitalizations, diuretic dose, mitral regurgitation, pulmonary artery pressure, plasma volume, heart rate, serum brain natriuretic peptide levels, and the inflammatory markers C reactive protein and Interleukin 6, and an improvement in New York Heart Association class, exercise capacity, oxygen utilization during exercise, sleep apnea, caloric intake, depression, and quality of life. The activity of endothelial progenitor cells was also increased. Iron deficiency may also play an important role in the anemia, because significant improvement of cardiac, renal, and functional status in these anemic CKD-CHF has been seen after treatment with IV iron alone. Clearly more work is needed to clarify the relationship between anemia, CKD and CHF.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Renal Insufficiency, Chronic

Anemia of chronic kidney disease due to deficiency of erythropoietin is common and has clinical consequences. Erythropoiesis stimulating agents including darbepoetin alfa (DA) are effective in correcting anemia. DA is generally well tolerated and has side effect profile similar to recombinant human erythropoietin. It has a long half-life permitting infrequent dosing. DA has been tested extensively in preclinical and clinical studies and significant experience has accumulated in clinical practice. Global safety profile of DA must consider recent data indicating worse survival, poor cardiovascular outcomes and thrombotic risks of targeting near normal hemoglobin levels and administering high doses of erythropoiesis stimulating agents. Strategies to achieve and maintain a reasonable, individualized target hemoglobin level with minimal variations in hemoglobin level are needed.

Topics: Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Anemia is a common feature of chronic kidney disease, but the management of anemia in children is complex. Erythropoietin and supplemental iron are used to maintain hemoglobin levels. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) clinical practice guidelines for the management of anemia specifically in children were recently published. Pediatric nephrologists are encouraged to use current clinical practice guidelines and best evidence in conjunction with their clinical experience to optimally manage patients with anemia.

Topics: Adolescent; Anemia; Child; Child, Preschool; Dietary Supplements; Erythropoietin; Female; Hemoglobins; Humans; Infant; Iron Compounds; Male; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

The purpose of this paper is to provide an overview of the current therapeutic options afforded to anemic chronic kidney disease (CKD) patients and the costs of these interventions.. Literature search of articles within Ovid MEDLINE between 1996 and 2007 that pertained to the treatment of anemia in chronic kidney disease patients.. Early detection and treatment of anemia associated with CKD has proven to provide positive cognitive and physical effects. Treatment options that increase iron storage and availability within the body and production of erythropoietin can assist in anemic CKD patients in achieving recommended levels of hemoglobin. Acknowledgement of the potential side effects associated with the medications selected to treat anemia can help in avoiding additional injury to the patient and thus reduce healthcare expenditure. A limitation of this review is that the search was performed within a single database.. Health care providers can play an active role in detecting anemia early and optimizing available treatment options. Future research on the effects of erythropoiesis-stimulating agents (ESA) on patients before they need dialysis, and a cost analysis between epoetin and darbepoetin alpha, would be beneficial.

Topics: Anemia; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Health Care Costs; Hematinics; Humans; Iron; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

The mortality rate in diabetics with chronic kidney disease (CKD) is seven times higher than end-stage renal disease mainly because of cardiac causes. Anaemia may have a relevant role in the pathogenesis of cardiovascular (CV) disease in CKD. Anaemia occurs at an earlier stage of CKD in diabetic individuals than in those with other causes of CKD. Observational findings support the unfavourable influence of anaemia on mortality in CKD patients, and the combination of anaemia and CKD in diabetics identifies a group with a particularly high mortality risk. While the effect of erythropoietin on these patients' quality of life is known, its impact on mortality and CV risk is uncertain. The recent Anaemia Correction in Diabetes (ACORD) trial in diabetic CKD patients, which targeted haemoglobin levels of 13-15 mg/dl, disclosed no statistically significant favourable or adverse effects on mortality or morbidity over the 2-year follow-up, while other studies endeavouring to nearly normalize haemoglobin have reportedly proved risky. Even if anaemia is causally involved, the pathogenesis of CV disease in diabetics with CKD is so complex that addressing just one factor (anaemia) may not suffice to prevent CV risk, and normalizing haemoglobin levels may even be harmful.

Topics: Anemia; Cardiovascular Diseases; Diabetic Nephropathies; Erythropoietin; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Risk

End stage renal disease (ESRD) affects over 1500 people per million population in countries with a high prevalence, such as the USA and Japan. Approximately two thirds of people with ESRD receive haemodialysis, a quarter have kidney transplants, and a tenth receive peritoneal dialysis.. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses and osmotic agents for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, dextrose solutions, erythropoietin, haemodialysis (standard-dose, increased-dose), high-membrane-flux haemodialysis, icodextrin, increased-dose peritoneal dialysis, low-membrane-flux haemodialysis, mupirocin, sevelamer, and standard-dose dialysis.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Renal Insufficiency, Chronic

The recombinant human erythropoietins epoetins alfa and beta have relatively short half-lives ( approximately 24 h by subcutaneous route) and have traditionally been administered 2 or 3 times a week for the treatment of anaemia in patients with chronic kidney disease. However, multiple weekly injections are inconvenient for both the patient and the healthcare provider. With the introduction of the longer-acting erythropoiesis-stimulating agent darbepoetin alfa, there has been growing interest in longer dosing intervals for erythropoiesis-stimulating agents. Data from several randomized studies have shown that darbepoetin alfa is effective in maintaining haemoglobin levels when administered (subcutaneously, intravenously or both) every 2 weeks in dialysis patients, and every 2 weeks or monthly in patients with chronic kidney disease not yet receiving dialysis. Moreover, intravenous administration with darbepoetin alfa does not require a higher dosage compared with the subcutaneous route. Epoetins alfa and beta have also been studied in similar schedules, although few data from well-designed studies are available. Current data suggest that once-weekly administration of these forms of epoetin is feasible in dialysis patients, but dose increases are often required when switching patients from traditional twice- or thrice-weekly schedules. Also, administration of epoetins every other week is feasible in selected patients with chronic renal insufficiency. Further study is required to clarify the optimum schedule for epoetins in these settings.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Economics, Pharmaceutical; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers.

Topics: Anemia; Erythropoietin; Humans; Iron; Nephrology; Recombinant Proteins; Renal Insufficiency, Chronic

Anemia in children with chronic kidney disease (CKD) is common secondary to inadequate erythropoietin production, iron deficiency, blood loss, inflammation, secondary hyperparathyroidism, uremic toxins, and nutritional deficiencies. Anemia has a variety of deleterious consequences, including associations with increased mortality and left ventricular hypertrophy. Recombinant human erythropoietin is effective in treating anemia in children with CKD, and recent studies show that darbepoetin alpha is an attractive alternative because it requires less frequent injections. Iron deficiency is a major cause of anemia that is resistant to erythropoietin or darbepoetin alpha. Although oral iron is effective in some patients, many children, especially those receiving hemodialysis, require intravenous iron to replenish their iron stores. Both acute dosing and chronic dosing of intravenous iron are effective in pediatric patients.

Topics: Anemia; Child, Preschool; Erythropoietin; Hematinics; Humans; Iron; Renal Insufficiency, Chronic

To determine whether or not Darbepoetin alpha (DA) was non-inferior to recombinant human erythropoietin (rHuEPO) in the treatment of anemia in children with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis). This was a randomized, open-label, two-arm, parallel group, active-controlled, non-inferiority trial conducted at a tertiary care center in New Delhi, India. Fifty patients of either gender (aged 1-18 years) with CKD stage 3-5 (on or not on dialysis) who had baseline hemoglobin (Hb) between 9 and 12 g/dL and were on stable erythropoietin therapy for at least 8 weeks were randomized (1:1) to either continue rHuEPO or switch to DA therapy for a period of 28 weeks. Doses were titrated in the initial 23 weeks to maintain the Hb between 11 and 12 g/dL, and efficacy was assessed between weeks 24 and 28. The primary efficacy outcome was the mean change in Hb between baseline and the evaluation period. In the intention-to-treat population (n = 50), the adjusted between-group difference in mean Hb change between the baseline and the evaluation period was 0.131 g/dL (95% CI: - 0.439 to 0.719, p = 0.629). The lower limit of the two-sided 95% CI for the difference in the mean change in Hb between the two treatment groups was well above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar pattern of non-inferiority was seen for per protocol population. The safety profile of DA and rHuEPO was also comparable (injection site pain:rHuEPO-3, DA-7; p-0.296).   Conclusion: DA is non-inferior to rHuEPO for the treatment of anemia of CKD (stage 3-5) in pediatric population with a comparable safety profile.   Trial registration: ClinicalTrials.gov Identifier: NCT04959578 (retrospectively registered), Date: July 13, 2021. What is Known: • Limited studies showing darbepoetin alpha is effective in children as an erythropoiesis stimulating agent. • No RCT from Indian subcontinent addressing this topic. What is New: • Darbepoetin alpha is non inferior to recombinant human erythropoietin for treatment of anemia in children with CKD stage 3-5 (on or not on dialysis) with safety comparable to recombinant human erythropoietin. • A cost reduction of approximately 8.6% per patient by shifting to darbepoetin alpha.

Topics: Adolescent; Anemia; Child; Child, Preschool; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; India; Infant; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

The optimum starting dose of intravenous continuous erythropoietin receptor activator (C.E.R.A.) has been previously determined; this study ascertains the optimum starting dose of subcutaneous C.E.R.A. administration in pediatric patients.. Phase 2, open-label, single-arm, multicenter study.. Patients aged 3 months to 17 years with renal anemia and chronic kidney disease (CKD; including those treated with maintenance dialysis and those not treated with dialysis) who were receiving maintenance treatment with erythropoiesis-stimulating agents (ESAs).. Subcutaneous C.E.R.A. administration every 4 weeks (starting dose was based on defined conversion factors).. The primary outcome was the change in hemoglobin concentration between the baseline and evaluation period for each patient. Secondary efficacy measures and safety were also evaluated.. Forty patients aged 0.4-17.7 years were enrolled. The study achieved its primary outcome: the mean change in hemoglobin concentration was an increase of 0.48g/dL; the 95% confidence interval (0.15-0.82) and standard deviation (±1.03) were within the prespecified boundaries (-1 to 1g/dL and<1.5g/dL, respectively). Mean hemoglobin concentrations were maintained within the target 10-12g/dL range in 24 of 38 patients and within±1g/dL of the baseline in 19 of 38 patients, and the median C.E.R.A. subcutaneous dose decreased over time. Efficacy in key subgroups (age group, dialysis type, prior ESA treatment) was consistent with the primary outcome. Thirty-eight patients completed the core period; 25 chose to enter the safety extension period. Safety was consistent with prior studies, with no new signals.. Single-arm and open-label study; small sample size.. Pediatric patients with anemia secondary to CKD who were on, or not on, dialysis could be safely and effectively switched from maintenance ESAs to subcutaneous C.E.R.A. administered every 4 weeks, using defined dose-conversion factors to determine the optimum starting dose.. F. Hoffmann-La Roche Ltd.. The SKIPPER trial registered at ClinicalTrials.gov with study number NCT03552393.. Anemia, a complication of chronic kidney disease, is associated with poor quality of life and an increased risk of hospitalization and mortality. The current treatments for anemia include iron therapy and erythropoiesis-stimulating agents (ESAs); however, the relatively short half-lives of the ESAs epoetin alfa/beta or darbepoetin alfa may require more frequent dosing and hospital visits compared with the ESA known as continuous erythropoietin receptor activator (C.E.R.A.). A previous study demonstrated that children aged 5 years or more with anemia associated with chronic kidney disease who were on hemodialysis could be switched to intravenous C.E.R.A. from their existing epoetin alfa/beta or darbepoetin alfa treatment. This study provides evidence that subcutaneous C.E.R.A. can safely and effectively treat anemia in children, including those aged<5 years and regardless of whether they were on dialysis or the type of dialysis they received (peritoneal dialysis or hemodialysis).

Topics: Anemia; Child; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa.. This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia.. Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant.. These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia.. ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017).. gov Identifier: NCT03350347 (November 22, 2017).

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Patient Satisfaction; Renal Insufficiency, Chronic

Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear.. We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36).. Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively.. In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis.. A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level < 10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Prespecified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed.. Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients.. Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.

Topics: Anemia; Darbepoetin alfa; Egypt; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important.. The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28-52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials.. Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin-angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials.. ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Male; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic

Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported.. To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients.. This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete.. Randomized 1:1 to daprodustat or darbepoetin alfa.. The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability.. A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa.. This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population.. ClinicalTrials.gov Identifier: NCT03029208.

Topics: Anemia; Barbiturates; Darbepoetin alfa; Erythropoietin; Female; Glycine; Hematinics; Hemoglobins; Humans; Iron; Male; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

A phase 3 study to assess the efficacy and safety of the desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, against the epoetin alfa for the treatment of anemia in patients with chronic kidney disease (CKD) with dialysis dependency.. DREAM-D was a phase 3, multicenter, open-label, randomized, active-controlled clinical study conducted across 38 centers in India. A total of 392 patients with clinical diagnosis of anemia due to CKD with dialysis need (Erythrocyte Stimulating Agent [ESA] naïve or prior ESA users) and with baseline hemoglobin levels of 8.0-11.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat oral tablets (thrice a week) or epoetin alfa subcutaneous injection for 24 weeks to maintain a hemoglobin level of 10-12 g/dL. The primary endpoint was to assess the change in the hemoglobin level between the desidustat and the epoetin alfa groups from the baseline to evaluation period week 16-24. The key secondary efficacy endpoint was the number of patients with hemoglobin response.. The least square mean (standard error) change in hemoglobin from the baseline to week 16-24 was 0.95 (0.09) g/dL in the desidustat group and 0.80 (0.09) g/dL in the epoetin alfa group (difference: 0.14 [0.14] g/dL; 95% confidence interval: -0.1304, 0.4202), which met the prespecified noninferiority margin. The number of hemoglobin responders was significantly higher in the desidustat group (106 [59.22%]) when compared to the epoetin alfa group (89 [48.37%]) (p = 0.0382). The safety profile of the desidustat oral tablet was comparable with the epoetin alfa injection. There were no new risks or no increased risks seen with the use of desidustat compared to epoetin alfa.. In this study, desidustat was found to be noninferior to epoetin in the treatment of anemia in CKD patients on dialysis and it was well-tolerated. Clinical Trial Registry Identifier: CTRI/2019/12/022312 (India).

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Quinolones; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being developed to treat anemia in patients with chronic kidney disease (CKD) without dialysis dependency.. In total, 588 patients with a clinical diagnosis of anemia due to CKD without dialysis need and with baseline hemoglobin of 7.0-10.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat 100 mg oral tablets thrice a week for 24 weeks or biosimilar darbepoetin subcutaneous injection 0.75 μg/kg once in 2 weeks for 24 weeks. The primary outcome was the change from baseline in hemoglobin to evaluation period of Weeks 16-24. Key secondary outcomes included the number of patients with hemoglobin response, changes in the hepcidin levels, changes in the vascular endothelial growth factor (VEGF) levels, and changes in the lipid and lipoprotein profiles.. Hemoglobin change from baseline to Weeks 16-24 was 1.95 g/dL in the desidustat group and 1.83 g/dL in the darbepoetin group (difference: 0.11 g/dL; 95% CI: -0.12, 0.34), which met prespecified non-inferiority margin (-0.75 g/dL). The hemoglobin responders were significantly higher (p = 0.0181) in the desidustat group (196 [77.78%]) compared to the darbepoetin group (176 [68.48%]). The difference of change in hepcidin from baseline to Week 12 and Week 24 (p = 0.0032 at Week 12, p = 0.0016 at Week 24) and the difference of change in low-density lipoprotein from baseline to Week 24 (p value = 0.0269) between the two groups was statistically significant. The difference of change from baseline in VEGF to Weeks 12 and 24 between the two groups was not statistically significant.. Desidustat is non-inferior to darbepoetin in the treatment of anemia due to non-dialysis dependent CKD and it is well-tolerated.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Hepcidins; Humans; Quinolones; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Endothelial Growth Factor A

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA).. Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%).. Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated.. Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033.

Topics: Anemia; Double-Blind Method; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Prolyl-Hydroxylase Inhibitors; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production.. To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm.. In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events.. Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is noninferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy and cardiovascular (CV) safety.. We report the trial design, key demographic, clinical and laboratory findings, and baseline therapies of 2964 patients randomized in the open-label (sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome trials (CVOTs) and in the most relevant registries.. The median age of patients was 58 years, 43% were female; 67% were White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among randomized patients, 89% were receiving hemodialysis and 11% peritoneal dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses were noted in 64 and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries.. ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anemia with CKD G5D.This trial is registered with ClinicalTrials.gov: NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

This 36-week, open-label, single-arm, phase 3 study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia undergoing peritoneal dialysis. Molidustat was titrated every 4 weeks to maintain Hb levels within the target range (≥11.0 and <13.0 g/dL). The primary efficacy outcome was the responder rate, defined as the proportion of patients who met all of the following criteria: (1) mean Hb levels in the target range during the evaluation period (Weeks 30-36); (2) ≥50% of Hb values within the target range during the evaluation period; and (3) no rescue treatment before the end of the evaluation period. Overall, 51 patients received molidustat. The responder rate (95% CI) during the evaluation period was 54.9% (40.3, 68.9). Overall, 98.0% of patients experienced at least 1 adverse event during the study. No deaths were reported. Molidustat maintained Hb levels in the prespecified range in more than half of the patients and was well tolerated.

Topics: Anemia; Erythropoietin; Hematinics; Hemoglobins; Humans; Japan; Peritoneal Dialysis; Pyrazoles; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Triazoles

This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients.. Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized.. In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups.. Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.

Topics: Erythropoietin; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic

This study was carried out to evaluate the effect of pegylated erythropoietin and to compare its effects with the effects of darbepoetin alfa on anemia of chronic kidney patients on maintenance hemodialysis having erythropoietin hyporesponsiveness.. Forty adult patients of chronic kidney disease(CKD) with erythropoietin hyporesponsiveness undergoing maintenance hemodialysis were included in the study. These patients were randomly divided into two groups, Group A consisting of 20 patients who received Subcutaneous Pegylated erythropoietin at a dose of 0.6 mcg/kg body weight, once in every two weeks along with intravenous iron 100 mg/week for 3 months. Group B patients received subcutaneous darbepoietin alfa at a dose of 0.45 mcg/kg body weight once weekly along with iv iron 100mg /week for 3 months. Hematological, renal and inflammatory parameters such as erythrocyte sedimentation rate, C reactive protein, serum ferritin and transferrin saturation were measured at monthly intervals for three months, compiled and analyzed statistically.. At the end of the study, in group A there was a significant rise in the hemoglobin, haematocrit and transferrin saturation (p < 0.001 for each of them) while there was a significant decrease in serum ferritin levels (p<0.001). In group &B the increase in hemoglobin, haematocrit and transferrin saturation were not statistically significant (p>0.05), and also there was a significant rise in the serum ferritin levels at the end of the study (p< 0.05). The mean rise in hemoglobin between subsequent months was higher in group A as compared to group B which was statistically significant.. Pegylated erythropoietin is better than darbepoetin alfa in overcoming erythropoietin hyporesponsiveness and maintaining stable hemoglobin levels in CKD patients on maintenance hemodialysis.

Topics: Adult; Anemia; Darbepoetin alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics.. Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0-23), maintenance (Weeks 24-52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24-36).. A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD.. The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.

Topics: Adult; Anemia; Erythropoietin; Glycine; Hematinics; Hemoglobins; Humans; Picolinic Acids; Renal Dialysis; Renal Insufficiency, Chronic

There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.. This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m. Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.. In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.

Topics: Aged; Aged, 80 and over; Anemia; Cardiovascular Diseases; Drug Resistance; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Polyethylene Glycols; Prognosis; Renal Dialysis; Renal Insufficiency, Chronic

To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo.. We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs.. ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.

Topics: Acute Kidney Injury; Albuminuria; Double-Blind Method; Erythropoietin; Female; Gestational Age; Glomerular Filtration Rate; Humans; Hypertension; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Male; Recombinant Proteins; Renal Insufficiency, Chronic

Posttransplant anemia affects 30% to 45% of kidney transplant recipients and is associated with increased morbidity. However, there is lack of evidence about safe hemoglobin levels after erythropoietin treatment. Studies are needed to better understand the potential benefits and risks, as well as to define safe target hemoglobin ranges in these patients.. In this single-center exploratory, open-label randomized controlled trial, kidney trans-plant recipients with anemia 3 months posttransplant were either treated with epoetin beta to a hemoglobin target level of 11.5 to 13.5 g/dL (n = 28) or given no treatment (n = 27). Treatment effects on graft function and health quality of life were assessed.. After 2 years, hemoglobin concentrations were significantly higher in the epoetin beta treatment group than in the no treatment group (12.3 ± 0.18 vs 9.99 ± 0.22 g/dL; P < .0001). Estimated glomerular filtration rate, calculated by Modified Diet in Renal Disease 7, declined by 1.7 mL/min (interquartile range, -6 to 4.24) in the epoetin treatment group and by 4.16 mL/min (interquartile range, -12.42 to 2.78) in the no treatment group (P = .32). Rate of progression, determined by estimated glomerular filtration rate slope, was not significantly different between groups (-0.09 ± 0.1 vs -0.12 ± 0.15 mL/min for treated vs not treated; P = .78). Moreover, we observed no significant differences in proteinuria and blood pressure. Treated patients had greater improvements in the vitality and mental health domains of the Medical Outcomes Short Form Health Survey quality of life scores.. Treatment of anemia in kidney transplant recipients to a hemoglobin level of 11.5 to 13.5 g/dL with erythropoietin improves some quality of life scores. The treatment was safe and not associated with adverse outcomes. There were no changes in rate of decline of graft function.

Topics: Anemia; Biomarkers; Disease Progression; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Kidney; Kidney Transplantation; London; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD.. We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513.. In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15,. In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

Topics: Aged; Anemia; Cardiovascular Diseases; Cause of Death; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Peptide Fragments; Recombinant Proteins; Renal Insufficiency, Chronic; Treatment Outcome

Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule.. 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days.. Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an E. These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen.. ClinicalTrials.gov Identifier: NCT02689206 ; date registered: 02/11/2016.

Topics: Aged; Aged, 80 and over; Anemia; Barbiturates; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors; Erythropoietin; Female; Ferritins; Glycine; Hematinics; Hematopoiesis; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Transferrin; Vascular Endothelial Growth Factor A

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis.. Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0-12.0 g/dL in reference to a dose adjustment algorithm (Period 2).. In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated.. Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis.

Topics: Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hematinics; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Japan; Kidney; Male; Middle Aged; N-substituted Glycines; Placebos; Pyridines; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome; Triazoles

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Inadequate response to Erythropoietin Stimulating Agents (ESA) despite using relatively larger doses regimen represents a potential risk factor of Cardiovascular (CV) related mortality in addition to health-care economic problems in anemic patients with Chronic Kidney Disease (CKD). Erythropoietin (EPO) hyporesponsiveness related to inflammation has been increased progressively. Melatonin is well known as a potent anti-inflammatory agent. Therefore, the current study was designed to evaluate whether melatonin could improve anemic patients response to EPO.. This single controlled clinical study was carried out in 41 CKD patients with hemoglobin (Hb) levels less than 11g/dl divided randomly in a 1:1 ratio into 2 groups; treatment group who received 5mg melatonin plus their regular treatments and control group who received their regular treatments only. Hematological and iron status parameters include Hb level, serum iron (S. iron), Transferrin Saturation Ratio (TSAT) and serum ferritin (S. ferritin) in addition to inflammatory parameters that include tissue necrotic factor alfa (TNF-α), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) determined before and after 12 weeks of treatment.. Melatonin remarkably increases the Hb level with a significant increase in S. iron and TSAT compared to baseline. The elevation of S. iron and TSAT was significantly higher in the melatonin group. Additionally, all inflammatory markers estimated were reduced significantly by melatonin compared to base line and control group.. The results of the current study showed that melatonin has an advantageous effect on improving EPO response in anemic patients with CKD.

Topics: Anemia; Antioxidants; Biomarkers; Erythropoietin; Female; Hematinics; Humans; Inflammation; Male; Melatonin; Middle Aged; Renal Insufficiency, Chronic

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers.. This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution.. In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l. Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.

Topics: Administration, Oral; Adult; Anemia; Area Under Curve; Erythropoietin; Half-Life; Healthy Volunteers; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Prolyl-Hydroxylase Inhibitors; Proof of Concept Study; Pyrazoles; Renal Insufficiency, Chronic; Single-Blind Method; Triazoles; Young Adult

TP0463518 is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor developed to aid in the treatment of anemia associated with chronic kidney disease (CKD) and is expected to increase erythropoietin (EPO) derived from liver. Two phase I studies were conducted in healthy volunteers (HV) and CKD patients undergoing hemodialysis (i.e., HD patients) or those not undergoing dialysis (i.e., ND patients).. Pharmacokinetics, pharmacodynamics, and safety profiles of TP0463518 were assessed. Forty HV received single oral doses of TP0463518 at 3, 6, 11, 20, and 36 mg or placebo. Twenty ND patients received single doses of TP0463518 at 1, 6, and 11 mg and 9 HD patients received TP0463518 at 1 and 11 mg doses. To identify the source organ of EPO, glycosylation patterns were determined using percentage migrated isoform (PMI) values.. Declining renal function slowed elimination of TP0463518 and increased the mean AUC0-∞. ∆Emax of serum EPO in 11-mg groups of HV, ND patients, and HD patients were 24.37 ± 11.37, 201.57 ± 130.34, and 1,324.76 ± 1,189.24 mIU/mL respectively. A strong correlation was -observed between logarithm conversions of ∆Emax and AUC0-∞ with correlation coefficients of 0.945. PMI values of blood after TP0463518 administration were elevated to similar or higher levels in comparison with those of umbilical cord blood, which mainly contains liver-derived EPO.. TP0463518 induced dose-dependent EPO production, mainly derived from the liver in HV and CKD patients. These results suggest that TP0463518 is a new strategy for treating anemia in CKD, which can be used regardless of renal functions.

Topics: Administration, Oral; Adult; Aged; Anemia; Area Under Curve; Dihydropyridines; Dose-Response Relationship, Drug; Erythropoietin; Female; Glomerular Filtration Rate; Healthy Volunteers; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Liver; Male; Middle Aged; Pyridines; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Young Adult

Thirty adult patients of end stage renal disease with erythropoietin hyporesponsiveness undergoing maintenance hemodialysis were included in the study. Patients were divided randomly into two groups of 15 patients each. Group A were given atorvastatin in a dose of 20 mg once daily for a period of 4 months along with erythropoietin 6000 IU S/C and IV iron 100mg twice weekly after each hemodialysis. Group B was given erythropoietin 6000 IU S/C and IV iron 100 mg twice weekly after each hemodialysis without addition of atorvastatin for 4 months. Hematological, renal parameters, inflammatory parameters such as erythrocyte sedimentation rate, highly sensitive C reactive protein, serum ferritin and erythropoietin resistance index were done at baseline and then two monthly intervals for 4 months.. At the end of study, in group A hemoglobin and haematocrit significantly increased (p <0.001 for both) while HsCRP, ESR and erythropoietin resistance index decreased significantly (p=0.001, 0.001 and <0.001 respectively). In group B, the increase in hemoglobin and haematocrit were not statistically significant (p >0.05) similarly fall in HsCRP and ERI were also not significant statistically (p >0.05). The mean rise in hemoglobin between subsequent months was higher in group A as compared to group B which was statically significant.. Statin can be used as an adjuvant to erythropoietin in management of anemia in patients of chronic kidney disease, who show hyporesponsiveness to increased doses of erythropoietin, by its anti-inflammatory properties.

Topics: Adult; Anemia; Atorvastatin; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic

Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD.. A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability.. Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration.. Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.

Topics: Adult; Aged; Anemia; Biomarkers; C-Reactive Protein; Cholesterol; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Ferritins; Glycine; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Middle Aged; Picolinic Acids; Renal Insufficiency, Chronic; Vascular Endothelial Growth Factor A

HbA1c is the most accepted laboratory parameter for the long term observation of glucose control. There is still much of a debate about the use of HbA1c as a metabolic indicator in diabetic patients (DM) on haemodialysis (HD) and erythropoiesis-stimulating agent (ESA) therapy because of the altered erythrocyte turn over in patients with chronic kidney disease and haemodialysis (CKD5D). In 102 CKD5 patients with and without diabetes mellitus, we examined the dose dependent variability in HbA1c and fructosamine levels under haemodialysis and treated with epoetin α (n=48) and a new generation agent with continuous stimulation of methoxy polyethylene glycol epoetin beta (C.E.R.A.; n=54). HbA1c levels were affected by therapy with ESA treatments. ESA dose was inversely correlated with HbA1c and an escalation of 10.000 IU per week induced an estimated decrease of HbA1c of 0.6 percent. In addition, the increase of reticulocyte number as a marker for erythropoiesis was significantly inversely correlated with the increase of ΔHbA1c. ESA treatments had no such effect on the alternative metabolic parameter fructosamine. When compared, both therapeutic agents had comparable success in attaining haemoglobin (Hb) target values. C.E.R.A. showed better correlation and was more effective over a longer dose interval. Our results show that HbA1c levels in patients should be carefully interpreted based on interfering factors. Nevertheless, HbA1c is currently the most consistent parameter for use ascertaining metabolic status of patients suffering from diabetes mellitus.

Topics: Adult; Aged; Aged, 80 and over; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Fructosamine; Glycated Hemoglobin; Hematinics; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

C.E.R.A. reported effective correction of anaemia and was well tolerated in International studies on CKD patients not on dialysis.. The study aimed to describe the management of renal anaemia in CKD patients not on dialysis with C.E.R.A. in routine clinical practice in India.. This was a prospective, single-arm, open-label, multi-centre, non-interventional, Phase IV study which followed 108 CKD Stage III-IV patients, not on dialysis with Hb < 10 g/dL for correction of anaemia with C.E.R.A.. Of the 108 patients with Hb < 10 g/dL at baseline, 83 (90.2%) patients achieved target Hb of 10-12 g/dL and the time taken to achieve correction of anaemia was 9.6 weeks ± 6.13 weeks in the Intent-to-treat population. Haemoglobin concentration increased from 8.59 ± 0.808 g/dL pre-therapy to 10.91 ± 0.634 g/dL post-therapy. The change in mean ± SD Hb value was 2.32 ± 0.174 g/dL. Maintenance of Hb levels within the target range of Hb 10 - 12 g/dL was observed in 78.2% of ITT and 80.8% of the PP population for mean duration of 16.69 weeks. Four patients (3.7%) experienced 5 AEs and 2 patients (1.9%) experienced 3 SAEs in the safety population. As per the treating physician none of the AEs or SAEs was considered related to study drug. There were no deaths reported.. This study demonstrated successful correction of anaemia in Indian patients with C.E.R.A. treatment as well as maintenance of Hb levels within the target range. C.E.R.A. was well tolerated with no new safety concerns specific to the Indian population. The less frequent up to monthly dosing schedule of C.E.R.A. may offer clinicians and patients a simplified regimen of anaemia management as compared to traditional frequently administered (thrice weekly to once weekly) ESAs.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Renal Insufficiency, Chronic

Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated.. We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated.. Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL.. Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels.

Topics: Aged; Anemia; Barbiturates; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Glycine; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Japan; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Vascular Endothelial Growth Factor A

It is unknown whether early intervention with low-dose erythropoiesis-stimulating agents (ESAs) in non-anaemic patients delays progression of chronic kidney disease (CKD).. In a single-blind, 24-month trial, adults with estimated glomerular filtration rate (eGFR) 30–59 mL/min/1.73 m2 and either Type 2 diabetes mellitus or previous kidney transplantation were randomized to low-dose continuous erythropoiesis receptor activator (CERA; monthly dose 30–75 µg; n = 115) or placebo (n = 120). The primary endpoint was the annual change in eGFR (abbreviated Modification of Diet in Renal Disease formula).. Mean (standard deviation) eGFR was 40.7 (9.8) mL/min/1.73 m2 versus 39.8 (9.2) mL/min/1.73 m2 at baseline for CERA and placebo, respectively, and 39.0 (11.6) g/dL versus 39.7 (10.6) g/dL at the final visit. The median (interquartile range) annual reduction in eGFR was 0.5 (−2.2, 3.8) mL/min/1.73 m2 with CERA versus 0.4 (−2.0, 3.2) mL/min/1.73 m2 with placebo (P = 0.657). No significant difference in the annual change in eGFR was observed between treatment groups in the subpopulations with Type 2 diabetes or kidney transplant. Adverse events with a suspected relation to study drug occurred in 22.0% and 16.2% of patients randomized to CERA or placebo, respectively, and adverse events led to study drug discontinuation in 11.0% and 8.5% of patients.. Patients with moderate CKD and Type 2 diabetes or previous kidney transplantation showed stable renal function that was unaffected by administration of low-dose ESA. In addition, there was no clinically meaningful effect of 2-year low-dose ESA treatment on albuminuria, an important surrogate marker of kidney injury.

Topics: Anemia; Diabetes Mellitus, Type 2; Disease Progression; Erythropoiesis; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Single-Blind Method

Contrast-induced-nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease.. A prospective, randomized, controlled trial was carried out in 138 diabetic patients with eGFR <60 mL/min who underwent non-urgent CA ± PCI. Patients received normal saline and n-acetyl cysteine before CA, with or without 50,000 U of EPO administered 30 min prior to CA. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL during the first 2 days after exposure to contrast media. Primary outcome was the incidence of CIN. Secondary outcomes were the sensitivity and positive predictive value (PPV) of Cystatin C (CC) and Neutrophil-gelatinase-associated-lipocalin (NGAL) for diagnosis of CIN.. The observed incidence of CIN was 8.7%, significantly lower than the expected for such high-risk population. The administration of EPO prior to CA did not reduce the incidence of CIN (9.7% vs. 7.6%, P = 0.65). CC and NGAL demonstrated a low sensitivity (16.6%) and low PPV (6.7 and 33.3%, respectively) for detecting CIN.. The administration of EPO prior to CA did not reduce the incidence of CIN. Additional prospective research with a larger sample size and in other patient categories is essential to further define the potential protective effect of EPO on prevention of CIN.

Topics: Acetylcysteine; Acute Kidney Injury; Aged; Aged, 80 and over; Biomarkers; Contrast Media; Coronary Angiography; Cystatin C; Cytoprotection; Diabetic Nephropathies; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Infusions, Intravenous; Iohexol; Israel; Lipocalin-2; Male; Middle Aged; Prospective Studies; Protective Agents; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Triiodobenzoic Acids

Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD.

Topics: Aged; Anemia; Barbiturates; Erythropoietin; Female; Glycine; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Single-Blind Method; Time Factors

Background. Cardiovascular morbidity and mortality are very high in patients with chronic kidney disease (CKD). The purpose of this study is to evaluate the impact of continuous erythropoietin receptor activator (CERA) on selected biomarkers of cardiovascular disease, left ventricle structure, and function in CKD. Material and Methods. Peripheral blood was collected from 25 CKD patients before and after CERA treatment and 20 healthy subjects. In serum samples, we assessed inflammatory markers (IL-1β, TNF-RI, TNF-RII, sFas, sFasL, MMP-9, TIMP-1, and TGF-β1), endothelial dysfunction markers (sE-selectin, sICAM-1, and sVCAM-1), and volume-related marker (NT-proBNP). All subjects underwent echocardiography and were evaluated for selected biochemical parameters (Hb, creatinine, and CRP). Results. Evaluated biomarkers and echocardiographic parameters of left ventricle structure were significantly increased but left ventricle EF was significantly decreased in CKD patients compared to controls. After CERA treatment, we observed a significant increase of Hb and left ventricle EF and a significant decrease of NT-proBNP and MMP-9. There was a significant negative correlation between Hb and TNF-RI, sICAM-1, and IL-1β. Conclusions. Our results indicate that selected biomarkers related to cardiovascular risk are significantly increased in CKD patients compared to controls. CERA treatment has anti-inflammatory action, diminishes endothelial dysfunction, and improves left ventricle function in these patients.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Female; Heart Ventricles; Humans; Inflammation Mediators; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Ventricular Function, Left

Erythropoiesis-stimulating agents (ESAs) are commonly used for the treatment of anemia due to chronic kidney disease (CKD) and end stage renal disease (ESRD). Patients often lack an understanding of the potential risks and benefits of ESAs, despite government mandated education on this topic. Decision aids are tools commonly used to discuss important information in health care settings. To address this knowledge gap, we designed this study to evaluate the effectiveness of a novel ESA decision aid at promoting informed shared decision making (ISDM) between patients and providers related to ESA use for CKD- and ESRD-related anemia.. Using the principles of informed shared decision making theory, we designed and piloted an ESA decision aid intended to increase CKD and ESRD patient understanding of the potential risks and benefits of ESAs. Informed by the findings during development, the ESA decision aid was modified and finalized for testing. We will perform a randomized clinical trial to assess if administration of the ESA decision aid improves patient understanding of the risks and benefits of ESA use compared to control patients receiving standard care. Participants with either CKD or ESRD and who are receiving ESAs will be eligible for participation. The primary outcome is patients' score on the Patient Anemia Knowledge in Kidney Disease (PAKKD) survey assessed at enrollment and 3 months after. Secondary outcomes include decisional conflict related to ESAs, and patient satisfaction with provider communication.. The Anemia Risk Communication for patients with Kidney Disease (ARC-KD) study will assess the effectiveness of a novel ESA decision aid to improve patient understanding of ESA use to manage CKD- and ESRD-related anemia. This decision aid is the first resource targeted to improve patient understanding of anemia management in the kidney health context. With the increasing options available for anemia management, this will serve as an important foundation to evolve in the future to optimize anemia-related shared decision making.. ClinicalTrials.gov, number NCT01992926 . Registered 11/14/2013.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Clinical Decision-Making; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Single-Blind Method; Treatment Outcome; Young Adult

Erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia is common in chronic kidney disease (CKD). Pentoxifylline shows promise as a treatment for ESA-hyporesponsive anemia, but has not been rigorously evaluated.. Multicenter, double-blind, randomized, controlled trial.. 53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin≤120g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk divided by hemoglobin concentration in g/L]≥1.0IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005μg/kg/wk/g/L for darbepoetin-treated patients).. Pentoxifylline (400mg/d; n=26) or matching placebo (control; n=27) for 4 months.. ESA resistance index at 4 months; secondary outcomes: hemoglobin concentration, ESA dose, blood transfusion requirement, serum ferritin level and transferrin saturation, C-reactive protein level, adverse events, quality of life, and health economics.. There was no statistically significant difference in ESA resistance index between the pentoxifylline and control groups (adjusted mean difference, -0.39 [95%CI, -0.89 to 0.10] IU/kg/wk/g/L; P=0.1). Pentoxifylline significantly increased hemoglobin concentration relative to the control group (adjusted mean difference, 7.6 [95%CI, 1.7-13.5] g/L; P=0.01). There was no difference in ESA dose between groups (-20.8 [95%CI, -67.2 to 25.7] IU/kg/wk; P=0.4). No differences in blood transfusion requirements, adverse events, or quality of life were observed between groups. Pentoxifylline cost A$88.05 (US $82.94) per person over the trial and produced mean savings in ESA cost of A$1,332 (US $1,255). The overall economic impact over the trial period was a saving of A$1,244 (US $1,172) per person for the pentoxifylline group compared with controls.. Sample size smaller than planned due to slow recruitment.. Pentoxifylline did not significantly modify ESA hyporesponsiveness, but increased hemoglobin concentration. Further studies are warranted to determine whether pentoxifylline therapy represents a safe strategy for increasing hemoglobin levels in patients with CKD with ESA-hyporesponsive anemia.

Topics: Adult; Aged; Anemia; Cost Savings; Double-Blind Method; Drug Monitoring; Drug Resistance; Drug Synergism; Erythropoiesis; Erythropoietin; Hematologic Agents; Hemoglobins; Humans; Middle Aged; Pentoxifylline; Quality of Life; Renal Insufficiency, Chronic; Vasodilator Agents

Anemia is a frequent complication in patients with chronic kidney disease. However, human recombinant erythropoietin (rHu-EPO) has revolutionized the management of anemia in chronically dialyzed patients. Epomax ® is a new rHu-EPO alfa manufactured in Tunisia (Medis Laboratories). The aim of this study was to evaluate the efficacy and tolerance of Epomax ® in chronic hemodialysis (HD) patients in a phase-III, multicenter, clinical trial. Fiftythree HD patients (mean age 47.7 ± 13 years) who received a stable dose of rHu-EPO (Hemax ® , a rHu-EPO alfa manufactured by Biosidus Laboratories) subcutaneously were switched to Epomax ® via the same route of administration. At baseline, the mean systolic pressure was 132 ± 18 mm Hg and the mean diastolic pressure was 79 ± 8 mm Hg. The mean blood hemoglobin was 10.2 g/dL and the median ferritin level was 667 ng/mL. After a follow-up of 43 days, the mean blood hemoglobin was 10.5 g/dL under the effect of Epomax ® . There was no significant difference in the mean hemoglobin levels between the treatments with both drugs. Few adverse events were reported during the study. We conclude that Epomax ® was effective at maintaining the hemoglobin levels at target concentrations and was well tolerated in HD patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Blood Pressure; Drug Substitution; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Therapeutic Equivalency; Tunisia

The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified.. Retrospective analysis of prospective randomized clinical trial.. We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo.. Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR).. Cause of death as adjudicated by a blinded committee.. Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles.. Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available.. In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Topics: Aged; Cardiovascular Diseases; Cause of Death; Cholesterol, HDL; Cholesterol, LDL; Darbepoetin alfa; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Multivariate Analysis; Renal Insufficiency, Chronic; Retrospective Studies; Triglycerides

Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects.. NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity.. Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo.. Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial.. Clintrials.gov #NCT00761657.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Glycine; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Prognosis; Renal Dialysis; Renal Insufficiency, Chronic; Single-Blind Method; Young Adult

Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly assigned to receive subcutaneous CERA or DA once every four weeks during 48 weeks. In both groups, the rate of achievement of target Hb level changed from 70% to 100% in weeks 0 to 48, with no significant difference between the groups. Compared with week 0, the Hb level was significantly increased from week 24 in the DA group and from week 8 in the CERA group. In addition, the reticulocyte count was significantly increased from week 4 in the CERA group compared with the DA group. There was no significant difference in the levels of estimated glomerular filtration rate and iron status between both groups. Because of the small number of patients in this study, only limited conclusions can be drawn. However, the results suggest that subcutaneous administration of DA or CERA once every four weeks to predialysis patients has similar effects on achievement of target Hb levels.

Topics: Aged; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic; Reticulocytes

The prevalence of chronic kidney disease (CKD) increases with age, and the risk of significant anaemia increases as renal function declines. The objectives of this study were to assess the effect of darbepoetin alfa administration on health-related quality of life (HRQOL) through treatment for anaemia in older patients with CKD.. In this multicentre, randomised, placebo-controlled trial, older patients (aged ≥ 70 years) with CKD (Stages 3-5, predialysis) and haemoglobin (Hb) < 11.0 g/dL were randomised to darbepoetin alfa (n = 28) or placebo (n = 23). HRQOL was measured using a number of instruments including Short Form-36 (SF-36) and Functional Assessment of Cancer Therapy-Anaemia (FACT-An).. The primary endpoint, mean SF-36 Vitality Score at Week 24, was comparable between the darbepoetin alfa (51.4 [95 % CI 48.0, 54.9]) and placebo (46.7 [40.9, 52.5]) groups. Darbepoetin alfa-treated patients experienced statistically significant improvements in some SF-36 and FACT-An Subscale Scores. Mean Hb was higher with darbepoetin alfa (12.5 [12.1, 12.9] g/dL) than with placebo (10.5 [10.1, 11.0] g/dL). The safety profiles were comparable between the treatment groups. The study was limited by only 20 % of the planned patient recruitment being achieved.. Darbepoetin alfa increased Hb and, within study limitations, suggested that improvements in some HRQOL domains in older CKD patients with anaemia may be achieved with more physiological haemoglobin.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Early Termination of Clinical Trials; Erythropoietin; Health Status; Hematinics; Hemoglobins; Humans; Male; Patient Selection; Quality of Life; Renal Insufficiency, Chronic; Single-Blind Method; Surveys and Questionnaires

Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a long-half life. This study investigated the efficacy of CERA for correcting anemia in Korean patients on dialysis. Patients (≥ 18 yr) who were not receiving any ESAs for more than 8 weeks were randomly assigned to either intravenous CERA once every 2 weeks (n=39) or epoetin beta thrice-weekly (n=41) during a 24-week correction phase. Hemoglobin (Hb) response was defined as increase of Hb by at least 1 g/dL and Hb ≥ 11 g/dL without red blood cell (RBC) transfusion. Median dialysis duration was 1.7 (0.3-20.8) and 1.6 (0.4-13.8) yr in CERA and epoetin beta group, respectively. Hemoglobin response rate of CERA was 79.5% (95% confidence interval [CI], 63.5-90.7). As the lower limit of 95% CI was higher than pre-specified 60% response rate, it can be concluded that CERA corrected anemia (P<0.05). Hb response rate of epoetin beta was 87.8% (95% CI, 73.8-95.9) (P=0.37). Median time to response was 12 weeks in CERA and 10.3 weeks in epoetin beta (P=0.03). It is suggested that once every 2 weeks administration of CERA is effective for correcting anemia in Korean patients on long-term hemodialysis with longer time-to-response than thrice weekly epoetin beta. (ClinicalTrials.gov registry No. NCT00546481).

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Republic of Korea

There is no consensus on the type, time of initiation, or duration of use of enteral nutrition in patients with chronic kidney disease (CKD). This study aimed to compare the effects of a renal-specific oral nutrition supplement (RS-ONS) and a standard recommended nutrition regime on biochemical and nutrition markers in malnourished patients with CKD on hemodialysis.. Sixty-two malnourished patients with CKD, divided into experimental (RS-ONS; n = 32; mean [SD] age, 62.0 [11.3] years; 55.2% female) and control (CON; n = 30; mean [SD] age, 57.2 [12.3] years; 31% female) groups, were evaluated for anthropometric, biochemical, and inflammatory parameters.. Mean (SD) serum albumin levels were significantly increased in the RS-ONS group from 3.5 (0.3) g/dL at baseline to 3.7 (0.2) g/dL at 6 months (P = .028). Significantly fewer patients had serum albumin levels of <3.5 g/dL after month 6. Dry weight of patients significantly increased in the RS-ONS but decreased in the CON groups (P < .001 for each). Percent change from baseline revealed negative results for bioelectrical impedance analysis (P < .001) in the CON group. Malnutrition inflammation score at 6 months (P = .006) and erythropoietin (EPO) dose requirements were higher in the CON group (P = .012).. Our findings indicate that consuming RS-ONS improves serum albumin and anthropometric measures, as well as reduces EPO dose, in patients with CKD.

Topics: Administration, Oral; Aged; Body Weight; Dietary Supplements; Electric Impedance; Erythropoietin; Female; Humans; Male; Malnutrition; Middle Aged; Nutritional Status; Renal Dialysis; Renal Insufficiency, Chronic; Serum Albumin

Maintaining target hemoglobin (Hb) with minimal variability is a challenge in hemodialysis (HD) patients. The aim of this study is to compare the long- and short-acting erythropoietin-stimulating agents such as Aranesp and Eprex in achieving these targets.. Randomized, prospective, open-labeled study of 24 weeks includes stable patients on HD >3 months, age >18 years, and on Eprex for >3 months. Patients were randomized into two groups: A-(Aranesp group):HD patients on Eprex Q TIW or BIW were converted to Aranesp Q weekly, by using the conversion factor of 200:1 and those on Eprex Q weekly to Aranesp Q 2 weeks; B-(Eprex group):patients continued on Eprex treatment. Hemoglobin target was set at (105-125 g/l). Primary end points were percentage of patients achieving target Hb, hemoglobin variability, and number of dose changes in each group.. This study consisted of 139 HD patients: 72 in the Aranesp and 67 in the Eprex-mean (SD) age 54 (16.2) years, 77 (55 %) males. About 46 % were diabetic. Target Hb achieved in 64.8 % of the Aranesp and 59.7 % in the Eprex (p = 0.006). Hb variability was less frequent in the Aranesp group (p = 0.2). Mean number of dose changes was 1.3 (0.87) in the Aranesp and 1.9 (1.2) in the Eprex (p < 0.001). There was 1 vascular access thrombosis in the Aranesp and 8 in the Eprex (p < 0.001). There was no difference in hospitalization and death number between the 2 groups.. Aranesp Q weekly or every 2 weeks is more efficient in achieving target Hb, with less dose changes and minor vascular access complications.

Topics: Adult; Aged; Darbepoetin alfa; Delayed-Action Preparations; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Hospitalization; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

While darbepoetin alfa (DA) can be administered once monthly (QM) to maintain haemoglobin (Hb) concentrations in anaemic patients with chronic kidney disease not on dialysis (CKD-ND), the QM use of DA for anaemia correction has not been previously investigated.. In this randomized, double-blind, non-inferiority, active-controlled study, adult subjects with CKD-ND, Hb levels <10 g/dL, and not treated with an erythropoiesis-stimulating agent were randomized 1:1 to receive DA every 2 weeks (Q2W) or QM for 33 weeks with initial doses of 0.75 μg/kg Q2W or 1.5 μg/kg QM. Subjects were treated to target Hb levels of 10-12 g/dL and ≥1 g/dL increase from baseline. The primary end-point was Hb change between baseline and the evaluation period (weeks 29-33), with a non-inferiority margin of -0.5 g/dL.. Three hundred and fifty-five subjects received ≥1 dose of DA. Mean (95% confidence interval [CI]) change in Hb between baseline and the evaluation period was 2.16 (1.98-2.33) g/dL for the Q2W group and 1.97 (1.80-2.14) g/dL for the QM group, the mean (95% CI) difference in Hb change being -0.19 (-0.43 to 0.05) g/dL. Most subjects (97.9% Q2W; 98.1% QM) achieved a Hb level ≥10.0 g/dL and ≥1.0 g/dL increase in Hb from baseline. Mean DA (SD) weekly equivalent doses over the evaluation period were 0.20 (0.23) and 0.27 (0.31) μg/kg per week for the Q2W and QM groups, respectively. Safety profiles were similar between groups.. In subjects with CKD-ND, QM dosing was non-inferior to Q2W dosing for anaemia correction and had a similar safety profile.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Australia; Biomarkers; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Male; Mexico; Middle Aged; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome; Up-Regulation; Young Adult

Anemia is a common complication among chronic kidney disease patients on hemodialysis, occurring mostly due to erythropoietin deficiency. This randomized noninferiority trial sought to compare the efficacy and safety of a new epoetin formulation developed by Bio-Manguinhos, a biologics manufacturer affiliated with the Brazilian government, with those of a commercially available product currently used in Brazil (a biosimilar epoetin formulation).. The sample size needed to enable demonstration of noninferiority with a statistical power of 85% for a between-group difference in hemoglobin levels of no more than 1.5 g/dL was calculated. In total, 74 patients were randomly assigned to receive the epoetin formulation from Bio-Manguinhos (n = 36) or the biosimilar epoetin formulation (n = 38) in a double-blind fashion. The inclusion criteria were current epoetin therapy and stable hemoglobin levels for at least 3 months prior to the study. The primary and secondary outcomes were mean monthly hemoglobin levels and safety, respectively. The dose was calculated according to international criteria and adjusted monthly in both groups according to hemoglobin levels and at the assistant physicians' discretion. Iron storage was estimated at baseline and once monthly. Clinicaltrials.gov: NCT01184495.. The study was conducted for 6 months after randomization. The mean baseline hemoglobin levels were 10.9±1.2 and 10.96±1.2 g/dL (p = 0.89) in the Bio-Manguinhos epoetin and biosimilar epoetin groups, respectively. During the study period, there was no significant change in hemoglobin levels in either group (p = 0.055, ANOVA). The epoetin from Bio-Manguinhos was slightly superior in the last 3 months of follow-up. The adverse event profiles of the two formulations were also similar.. The epoetin formulations tested in this study are equivalent in efficacy and safety.

Topics: Adult; Aged; Anemia; Biosimilar Pharmaceuticals; Brazil; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Iron; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

CERA, a continuous erythropoietin receptor activator, has reported effective correction of anaemia in international clinical trials.. Objective of this study was to evaluate efficacy and safety of CERA in Indian patients who were on dialysis and has not received erythropoiesis stimulating agent (ESA) therapy in last 8 weeks.. In this open label, single arm, prospective, multi-centre study, 189 patients on dialysis, having Haemoglobin (Hb) between 8 - 10 g/dL and not receiving any ESA for last 8 weeks were included at 14 centers across India. CERA was given intravenous (IV) at the dose of 0.6 microg/kg every two weeks. Primary end point of the study was mean change in Hb concentration from baseline to end of the treatment period (TP) of 16 weeks.. Mean change of Hb from baseline to end of TP was 2.11 +/- 1.37 g/dL and 2.08 +/- 1.29 g/dL in intent to treat (ITT) and per protocol (PP) population respectively. Mean time to achieve Hb response was 6.10 +/- 3.87 weeks and 6.16 +/- 3.92 weeks in ITT and PP populations respectively. Out of 68 adverse events (AEs) seen during study period, 33 were serious adverse events (SAEs). As per investigators all SAEs were related to underlying disease and not to the study medication.. It is concluded that CERA administered once in two weeks in dialysis patients effectively corrected chronic kidney disease (CKD) related anaemia and was well tolerated with no significant untoward effect directly related to drug therapy in Indian population.

Topics: Administration, Intravenous; Adult; Anemia; Drug Administration Schedule; Erythropoietin; Female; Humans; India; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Vitamin D insufficiency is related to erythropoietin resistance in chronic kidney disease (CKD). This study was conducted to evaluate the effect of ergocalciferol on the dose of erythrocyte-stimulating agent (ESA) administered to children with CKD stage 5 and vitamin D insufficiency.. Twenty patients aged <18 years with CKD stages 5 or 5D and vitamin D insufficiency were divided into two groups. During the 12-week study, ten patients received oral ergocalciferol (treatment) whereas the other ten patients did not (control). The ESA dosage was recorded monthly.. There were no significant differences in demographic data, ESA dosages, and laboratory data, including corrected calcium, phosphorus, parathyroid hormone, hemoglobin, ferritin, 25-hydroxyvitamin D (25D), and transferrin saturation levels, between the two groups at baseline. At the completion of the study, serum 25D levels in the treatment group were significantly increased from baseline (p = 0.02) and were significantly higher than the serum 25D levels in the controls (p < 0.005). The ESA dosage in the treatment group was significantly decreased when compared to baseline (p = 0.04).. Vitamin D deficiency should be routinely detected and treated. Our results show that the administration of ergocalciferol in conjunction with 1,25-dihydroxyvitamin D3 reduced the dose of ESA required to treat children with CKD stages 5 and 5D and may decrease erythropoietin resistance.

Topics: Administration, Oral; Adolescent; Analysis of Variance; Anemia; Biomarkers; Child; Child, Preschool; Drug Resistance; Epoetin Alfa; Ergocalciferols; Erythropoietin; Female; Hematinics; Humans; Male; Prospective Studies; Recombinant Proteins; Renal Insufficiency, Chronic; Severity of Illness Index; Thailand; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

SureClick® is a prefilled pen for administration of darbepoetin alfa (DA) that is ready-to-use. We explored patient satisfaction with SureClick® compared with prefilled syringes (PFS).. Multicenter, prospective, 6-months, observational study in non-dialyzed patients with chronic kidney disease (CKD) treated with DA in PFS who switched to SureClick® at baseline. Main outcomes were: change in Anemia Treatment Satisfaction Questionnaire (ATSQ-S), Perceived Competence for Anemia Scale (PCAS) and self-administration rate.. We enrolled 132 patients with a mean(SD) age of 71.3 (14.6) years, 57.6% women. Mean(SD) ATSQ-S scores at baseline and final records were 25.5 (7.9) and 31.6 (4.9) (on a scale from 0 to 36 maximum satisfaction-, mean change: 6.2, 95%CI: 4.6-7.8, p<0.0001). The PCAS also increased significantly (4.3 (2.0) vs 5.6 (1.6), on a scale from 1 to 7 maximum competence, p<0.0001). At baseline 47.7% of patients self-administered DA with PFS, vs 74.2% with SureClick® (p<0.001). No significant changes in hemoglobin were observed (11.4 (0.5) vs 11.6 (1.3) g/dl, p=0.193). Two patients (1.5%) had adverse reactions to SureClick® (pain on application).. Our results suggest that the change from PFS to SureClick® could increase patient satisfaction and perceived competence in anemia management in non-dialyzed CKD patients, and could increase the self-administration rate, thereby reducing use of health resources.

Topics: Aged; Anemia; Darbepoetin alfa; Equipment Design; Erythropoietin; Female; Hematinics; Humans; Male; Patient Satisfaction; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Self Administration; Surveys and Questionnaires; Syringes

Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation.. We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis.. Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point.. In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.

Topics: Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Stroke; Treatment Outcome

Hemoglobin (Hb) variability is a common occurrence in hemodialysis patients treated with erythropoiesis-stimulating agents. High amplitude fluctuations have been associated with greater risk of morbidity and mortality.. This prospective, single centre pilot observational study was conducted over a 3-month period in daily practice patterns, to assess per-dialysis events and inter-dialysis complications that could interfere with erythropoiesis in patients undergoing hemodialysis.. Mean Hb levels remained stable in the 78 evaluable patients, as did darbepoetin alfa (DA) doses, including in patients suffering from diabetes or cardiac affections. In total, an average of 7.7 events / patient / month occurred, but no significant relationship with Hb excursions was shown.. The observation of 7.7 events per patient per month suggests a careful monitoring of Hb and DA dosing every other week, in order to maintain Hb level within the target.

Topics: Anemia; Biomarkers; Causality; Comorbidity; Darbepoetin alfa; Erythropoietin; Female; France; Hematinics; Hemoglobins; Humans; Incidence; Male; Middle Aged; Pilot Projects; Renal Dialysis; Renal Insufficiency, Chronic; Reproducibility of Results; Sensitivity and Specificity

There is data in the literature indicating increased oxidative stress in chronic kidney disease (CKD). Erythropoiesisstimulating agents (ESAs), which are commonly used to treat anemia in patients with CKD, seem to have an antioxidant action, which could be a part of nephroprotection. The aim of the current study was to investigate the effect of a long half-life ESA, methoxy polyethylene glycol-epoetin beta (Mircera), on some markers of oxidative stress in predialysis patients with CKD.. Peripheral blood was collected from 28 predialysis CKD patients 2 times, before Mircera treatment and after achieving target hemoglobin (Hb), and 15 healthy subjects (control group). Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in erythrocytes were measured according to commonly used methods as a function of the antioxidant defense system. To assess reactive oxygen species (ROS) production, malondialdehyde (MDA) concentration in erythrocytes and in plasma was measured according to a commonly used method.. SOD, GSH-Px, and CAT activity were similar, but plasma and erythrocyte MDA concentrations were significantly higher in CKD patients before ESA treatment in comparison to the control group. SOD, GSH-Px, and CAT activity was significantly higher, but plasma and erythrocyte MDA concentrations were significantly lower, in CKD patients after ESA treatment in comparison to these patients before treatment. We did not find a significant correlation between Hb concentration and SOD, GSH-Px, and CAT activity and plasma, as well as erythrocyte MDA concentrations. Analysis of all investigated groups showed a significant negative correlation between Hb concentration and plasma MDA concentration.. Our results suggest that treatment of anemia with methoxy polyethylene glycol-epoetin beta may inhibit oxidative stress in predialysis patients with CKD by enhancing the antioxidant defense system and reducing ROS production.

Topics: Catalase; Erythrocytes; Erythropoietin; Female; Glutathione Peroxidase; Hematinics; Humans; Injections, Subcutaneous; Male; Malondialdehyde; Oxidative Stress; Polyethylene Glycols; Reactive Oxygen Species; Renal Insufficiency, Chronic; Superoxide Dismutase

C.E.R.A. is a continuous erythropoietin receptor activator with characteristics that permit a once-monthly schedule of administration for the maintenance treatment for chronic kidney disease (CKD) patients. The main objective of this study was to assess the maintenance of Hb concentration with once-monthly intravenous and/or subcutaneous C.E.R.A. therapy in Latin American dialysis patients with chronic renal anemia previously treated with epoetin alfa s.c or i.v 1-3 times per week.. This was a single-arm, open-label, multicenter, 32-week study of anemic patients with CKD previously treated with epoetin alfa sc or iv 1-3 times per week. After a 4-week screening period, during which mean Hb levels were maintained between 10.5 and 12.5 g/dL on their previous erythropoiesis stimulating agent, eligible patients entered a 16-week C.E.R.A. dose titration period followed by a 4-week efficacy evaluation period (EEP) and a 28-week safety follow-up. The starting dose of C.E.R.A. was based on the previous dose of epoetin alfa. Doses of C.E.R.A. were then adjusted to maintain Hb levels within ±1.0 g/dL of the reference concentration and between 10.5 and 12.5 g/dL. The Hb reference concentration was defined as the mean of all Hb levels during screening. The primary end point was the proportion of patients maintaining a mean Hb concentration (g/dL) within ±1 g/dL of their reference Hb and between 10.5 and 12.5 g/dL during the EEP.. A total of 163 patients from 27 centers in Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, Uruguay, and Venezuela entered the treatment period and 102 completed the prescribed course of C.E.R.A. Forty-five patients (43.7 %) maintained a mean Hb concentration within ±1 g/dL of their reference Hb value and between 10.5 and 12.5 g/dL during the EEP. The median monthly dose remained constant at 120 μg during the titration period and during the EEP. On the average, there were only 2.3 dose changes per patient in 28 weeks of treatment, covering 7 C.E.R.A. scheduled administrations. 53 % of all dose changes were dose decreases, 47 % increases. A total of 10 AEs and 4 SAEs were considered to be related to the study treatment.. Once-monthly C.E.R.A. treatment effectively maintains stable Hb concentrations in patients with chronic renal anemia undergoing dialysis with a good safety and tolerability profile.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anemia; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Male; Mexico; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic; South America; Trace Elements; Young Adult

Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents.. Prospective clinical trial cohort.. 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL.. Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL.. 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level.. Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD.. In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.

Topics: Aged; Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic

Topics: Aged; Anemia; Biomarkers; Chi-Square Distribution; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Spain; Time Factors; Treatment Outcome

Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease.. We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3.. In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort.. Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).

Topics: Aged; Anemia; Antibodies; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Peptides; Renal Dialysis; Renal Insufficiency, Chronic

Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis.. In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 μg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point.. In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide.. The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).

Topics: Aged; Anemia; Antibodies; Cardiovascular Diseases; Darbepoetin alfa; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Peptides; Renal Insufficiency, Chronic

In the last ten years or so, there has been a steady increase in the number of patients with chronic kidney disease and those with end-stage renal failure who require some form of renal replacement therapy. Anemia is a well-known consequence of chronic kidney disease; its prevalence increases with the progression of renal failure and occurs in up to 95% of patients in the final stages of chronic kidney disease. In recent years, the greatest advance in the treatment of renal anemia has been made by the introduction of erythropoietin preparations, the application of which has significantly improved the patients' quality of life. The aim of this study was to analyze whether the treatment of renal anemia in chronic kidney disease patients not treated by dialysis affects the outcome of their treatment, reduces the incidence of cardiovascular diseases, delays the need of dialysis, reduces morbidity and mortality, and reduces the incidence of adverse cardiovascular events.. The study included patients with chronic kidney disease presenting for regular outpatient follow up at Department of Nephrology and Dialysis, Rijeka University Hospital Center. Patients were divided into two groups. Group 1 included patients whose renal anemia was treated with erythropoietin and group 2 patients whose anemia of chronic kidney disease was treated in any other way, regardless of the reason for the exclusion of erythropoietin. Each group included 31 patients with chronic kidney disease. During two years, each patient's laboratory parameters of chronic renal disease and renal anemia treatment were monitored at intervals not longer than six months. In addition, each patient's number of hospitalizations was recorded, taking into account the cause of hospitalization and the number of days spent in hospital.. During the two-year period, 62 patients with chronic kidney disease were analyzed (31 patients in the groups receiving and not receiving erythropoietin each). The mean age was 66 +/- 13.5 in the group receiving erythropoietin and 68 +/- 13.6 in the group not receiving erythropoietin. There were 70% of men and 30% of women in the former group, and 53% of men and 47% of women in the latter group. Examination for comorbid conditions (diabetes, hypertension, hyperlipoproteinemia and previous stroke) revealed no statistically significant differences between the two groups of patients. There were no statistically significant differences in changes of biochemical parameters (Fe, ferritin, CRP, albumin, calcium, phosphorus) between the two groups of patients during the two-year period either. There was no statistically significant between group-difference in the glomerular filtration rate after two years, but a tendency of slower progression of renal failure was observed in patients having received erythropoietin as compared to those who did not receive erythropoietin. Moreover, the number of hospitalizations due to adverse cardiovascular events was statistically significantly lower in patients that received erythropoietin, while there was no statistically significant difference in the total number of hospitalizations, hospitalizations for other indications (infection, bleeding, and worsening of renal failure), or total number of days spent in hospital, regardless of indication.. The number of patients with chronic kidney disease and those with end-stage renal failure requiring renal replacement therapy is increasing. Renal anemia, which occurs as a consequence of chronic kidney disease, is associated with increased morbidity and mortality, and with a reduced quality of life in these patients. Consequently, it is necessary to recognize this condition and apply appropriate treatment early in order to prolong life and improve the quality of life of patients with chronic kidney disease.

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Humans; Male; Recombinant Proteins; Renal Insufficiency, Chronic

Anaemia, the major sequelae of chronic renal disease (CRD) needs to be investigated because it acts as an independent risk factor for worsening of cardiovascular survival, cognitive impairment and poor quality of life. In this prospective tertiary care hospital-based study we have followed up 100 randomly assigned CRD patients who were not on dialysis for at least 6 months. Left ventricular mass index (LVMI), ejection fraction (EF), mini-mental status examination (MMSE) and general well-being of these patients were assessed quantitatively on admission and at 3rd and 6th months of follow-up after receiving recombinant human erythropoietin (rHuEPO) and aggressive intravenous iron therapy for anaemia correction. The median study duration was 6 years. Statistical analysis also showed the positive impact of anaemia correction which, even when partial, caused significant improvement in cardiovascular function as evidenced by increase in EF (p = 0.004) and decrease in LVMI (p = 0.016) along with substantial enhancement of general well-being (p < 0.001). Cognition did not show significant change within a short spell of 6 months. This study thus emphasises on earliest detection and correction of anaemia in CRD population to enhance both short-term and long-term survival as a whole.

Topics: Anemia; Erythropoietin; Female; Health Status; Heart Ventricles; Hemoglobins; Humans; Male; Mental Health; Renal Insufficiency, Chronic; Stroke Volume

HX575 is a biosimilar version of epoetin-α that is approved for the treatment of anemia associated with chronic kidney disease (CKD) using the intravenous route of administration. Here we report data from a study of anemic pre-dialysis patients to assess the safety, immunogenicity and efficacy of subcutaneous (s.c.) administration of HX575 vs. Erypo®/Eprex® (Ortho Biotech, Neuss, Germany).. This was a randomized, double-blind study in adult patients (n = 337) with Stage III - V CKD and a hemoglobin (Hb) level of 7.5 - 11.0 g/dl. Eligible patients were randomized to 52 weeks of treatment with HX575 or Erypo®/Eprex® at a starting dose of 25 IU/kg body weight 3 times weekly or 75 IU/kg body weight once weekly during Weeks 1 - 5. This could be adjusted after 5 weeks to maintain Hb levels between 10 and 12 g/dl. The primary objective was to assess the safety and immunogenicity of HX575 compared with Erypo®/Eprex®. Efficacy endpoints were mean absolute change in Hb from baseline to end of Week 13 and mean weekly epoetin dosage in Weeks 11 - 13.. HX575 was equivalent to Erypo®/Eprex® in terms of maintaining Hb levels and epoetin dose requirements. Two patients in the HX575 group developed neutralizing antibodies (NAbs) to erythropoietin, which resulted in the study being terminated prematurely. Aside from these two events, reported adverse events were as expected for patients with Stage III - V CKD and similar in both treatment groups.. This study demonstrated the efficacy and therapeutic equivalence of s.c. HX575 compared with the reference epoetin-α, but 2 patients developed NAbs during treatment with s.c. HX575 in this study. Results of a thorough root-cause analysis reported elsewhere indicate that increased tungsten exposure in pre-filled syringes precipitated immunogenic reactions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Antibodies; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency, Chronic; Young Adult

Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin level on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial.. Secondary analysis of a randomized controlled trial.. 1,432 participants with CKD and anemia.. Participants were randomly assigned to target hemoglobin levels of 13.5 versus 11.3 g/dL with the use of epoetin alfa.. Cox regression was used to estimate HRs for progression of CKD (a composite of doubling of creatinine level, initiation of renal replacement therapy, or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate, proteinuria, diabetes, heart failure, and smoking history) also were examined.. Participants randomly assigned to higher hemoglobin targets experienced shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03-1.52; P = 0.02) and multivariable models (HR, 1.22; 95% CI, 1.00-1.48; P = 0.05). These differences were attributable to higher rates of renal replacement therapy and death for participants in the high hemoglobin arm. Hemoglobin target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure (P > 0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (P = 0.04) such that the higher target had a greater risk of CKD progression for participants who currently smoked (HR, 2.50; 95% CI, 1.23-5.09; P = 0.01), which was not present for those who did not currently smoke (HR, 1.15; 95% CI, 0.93-1.41; P = 0.2).. A post hoc analysis; thus, cause and effect cannot be determined.. These results suggest that a high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anemia; Confidence Intervals; Disease Progression; Drug Delivery Systems; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hematinics; Hemoglobinometry; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Regression Analysis; Renal Insufficiency, Chronic; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Patients with chronic HCV infection have increased liver iron. Recently identified protein hepcidin synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. Lower erythropoietin and iron supplementation requirements were previously reported in HD patients with HCV infection. We investigated the association of prohepcidin with inflammation and iron parameters in HD patients with and without chronic HCV infection.. Sixty patients (27 male, 33 female, mean age 50±15 years) on chronic HD were included. Parameters related to iron metabolism (ferritin, serum iron and total iron binding capacity (TIBC)), inflammation (hs-CRP, TNF-α and IL-6) and prohepcidin levels were measured. The response to treatment (erythropoiesis-stimulating agent (ESA) resistance index) was assessed from the ratio of the weekly erythropoietin (rhuEPO) dose to hemoglobin (Hb) per unit weight.. Serum prohepcidin levels of HCV positive patients (135±25 ng/mL) were significantly lower than HCV negative patients [148±18 ng/mL, (p=0.025)]. Serum IL-6 levels of HCV positive patients were also significantly lower than HCV negative patients (p=0.016). Serum prohepcidin levels were positively correlated with ferritin (r=0.405, p=0.001) and IL-6 (r=0.271, p=0.050) levels in HD patients. In the HCV positive group, serum prohepcidin levels significantly correlated with ferritin levels (r=0.514 p=0.004). In the HCV negative group, serum prohepcidin levels significantly correlated with serum IL-6 levels (r=0.418, p=0.027). In multiple regression analysis performed to predict prohepcidin in HCV positive patients, serum ferritin was found to be an independent variable (r=0.28, p=0.008).. HCV positive HD patients have low levels of serum prohepcidin and IL-6 which might account for iron accumulation together with lower iron and rhuEPO requirements in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; Biomarkers; Cytokines; Erythropoietin; Female; Hepatitis, Chronic; Hepcidins; Humans; Iron; Male; Middle Aged; Protein Precursors; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

Continuous erythropoietin receptor activator (C.E.R.A.) is routinely given once every 2 weeks to correct hemoglobin (Hb) level, but monthly use is recommended in the maintenance phase.. In an open-label, single- arm, multicenter trial, 184 ESA-naïve non-dialysis patients with renal anemia (Hb ≤ 10.5 g/dl) received C.E.R.A. monthly from the start of therapy. The trial comprised a titration phase (Months 2 - 7) and an evaluation phase (Months 8 - 9). Mean Hb increased from 9.8 ± 0.7 g/dl at baseline to 11.5 ± 1.1 g/ dl during the evaluation phase (mean change 1.6 ± 1.1 g/dl; 95% CI 1.4 - 1.8 g/dl). Among patients with two Hb values available during the evaluation phase, 18.1% (19/105) were maintained at 11.0 - 12.0 g/dl and 49.5% (52/105) at 11.0 - 13.0 g/dl. 20 patients started dialysis and received C.E.R.A during the titration phase.. Their mean Hb increased from 10.6 ± 1.6 g/dl (last pre-dialysis value) to 11.3 ± 1.6 g/dl. Nine patients (4.9%) experienced one adverse event with a suspected relation to C.E.R.A.; 5 were graded serious. 54 patients (29.3%) discontinued the study (22 for adverse events).. Although no control arm was included, such that robust comparisons cannot be drawn, these results suggest that C.E.R.A. therapy can be initiated once a month in non-dialysis CKD patients with renal anemia without appearing to compromise the rate or degree of Hb correction.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Intention to Treat Analysis; Maintenance Chemotherapy; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

Anemia is a significant risk factor for patients with chronic kidney disease (CKD). Here, we investigated the effects of anemia correction on cardiac functions in CKD patients. Pre-dialysis CKD patients (n = 171) without known risk factors for cardiovascular disease (CVD) other than CKD with hemoglobin (Hb) concentrations < 10.0 g/dL were enrolled for evaluation of cardiac functions and biomarkers before and after the 16-week treatment of erythropoiesis-stimulating agents. The treatment significantly increased Hb concentrations in all patients who completed the study (n = 143, 8.91 ± 0.87 versus 11.27 ± 1.31 g/dL; n < 0.001) and among patients whose echocardiograms were available for evaluation (n = 77, 8.92 ± 0.94 versus 11.24 ± 1.13 g/dL; P < 0.001). The left ventricular mass index (LVMI) was decreased (121.3 ± 25.8 versus 114.7 ± 25.1 g/m(2), n = 77, P = 0.012) and significant correlation between the change in the LVMI and Hb concentration was noted (P = 0.011). The levels of B-type natriuretic peptide and human atrial natriuretic peptide, and the cardio-thoracic ratio were significantly increased among subjects with Hb concentrations < 11.0 g/dL at completion of the study. The changes in these parameters were significantly correlated with the Hb concentrations (P = 0.033, P = 0.011, and P < 0.001, respectively). No significant differences were observed in the electrocardiographic parameters. Correcting Hb levels higher than those conventionally recommended reduced left ventricular hypertrophy and myocardial stress, lowering risks for CVD in pre-dialysis CKD patients.

Topics: Aged; Anemia; Blood Pressure; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Female; Heart Function Tests; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Renal Insufficiency, Chronic

Subcutaneous injection of erythropoiesis-stimulating agents for the correction of anemia associated with chronic kidney disease is well recognized. Different delivery devices are available, although their impact on patient-reported outcomes is limited.. Subcutaneous delivery of darbepoetin alfa via an autoinjector prefilled pen (PFP) and prefilled syringe (PFS) were compared and assessed according to patient-rated preferences and perceptions.. In this single-center, randomized, open-label, double-crossover study, patients continued using the PFS for 4 injections or were switched to the PFP for the same number of injections, after which they were switched to the alternative device. Following further 4 injections using the new device, patients were switched back to the initial device. Questionnaires were administered at the end of each series of injections for each device and at the start and end of the study.. For overall device preference, the majority (62%) of patients responded with PFP, whereas 32% preferred the PFS mode of delivery. This preference for PFP was driven by a perception of increased convenience and ease of use compared with PFS. No significant differences in pain scores were noted between the 2 devices. Most patients rated both devices as being "easy" or "extremely easy" to use and were either "satisfied" or "extremely satisfied.". When given the choice, most patients preferred the PFP mode of administration compared with PFS due to convenience and ease of use. ClinicalTrials.gov identifier: ACTRN12611000839909.

Topics: Aged; Anemia; Cross-Over Studies; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Subcutaneous; Male; Middle Aged; Pain; Patient Preference; Patient Satisfaction; Renal Insufficiency, Chronic; Surveys and Questionnaires

Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis.. The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA).. MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without.. ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Atherosclerosis; Cardio-Renal Syndrome; Chi-Square Distribution; Contrast Media; Erythropoietin; Female; Fibrosis; Glomerular Filtration Rate; Heart Failure; Hematinics; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Meglumine; Middle Aged; Myocardium; Netherlands; Organometallic Compounds; Predictive Value of Tests; Prevalence; Prognosis; Renal Artery; Renal Artery Obstruction; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke Volume; Ventricular Function, Left

Comparison of efficacy of 12-month treatment of anemia in patients with chronic kidney disease (CKD) of stage III - IV with a long-acting drug darbepoetin alpha - aranesp and short-acting drug erythropoietin beta - recormon.. A total of 44 patients with CKD of stage III-IVwere divided into two groups. Of them, 24 had chronic glomerulonephritis and 20 had tubulointerstitial nephritis with verified nephrogenic anemia. Group 1 consisted of 22 patients given long-acting erythropoetin (darbepoetin alpha) in an initial dose 0,75 mcg/kg each 2 weeks subcutaneously. Group 2 consisted of 22 patients matched by age, gender, severity of anemia and renal failure with group 1 patients given short-acting erythropoietin (erythropoietin beta) in an initial 20 IU 3 times a week subcutaneous, for 12 months. In the phase of anemia correction and supporting therapy the levels of packed red blood cells, Hb, free serum ferrum, ferritin, percentage of iron in transfusion, serum albumin in blood serum, creatinin, glomerular filtration rate were examined monthly. The patients themselves daily measured blood pressure, diuresis, body mass.. The target level of Hb 110-120 g/l was achieved faster in group 2 than in group 1 (3 and 4 months, respectively). p < 0.05). In the phase of supporting a target Hb level, on the opposite, darbepoetin alpha provided more stable hemopoetin effect than erythropoietin beta, darbepoetin alpha median dose being constant in the course of the study.

Topics: Adolescent; Adult; Aged; Anemia; Blood Pressure; Darbepoetin alfa; Delayed-Action Preparations; Diuresis; Drug Administration Schedule; Erythropoietin; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index; Treatment Outcome; Young Adult

Neutrophil-gelatinase associated lipocalin (NGAL), a tubular injury marker, is associated with iron metabolism in hemodialysis patients. We investigated whether serum NGAL levels reflect iron metabolism in combined chronic heart failure and chronic kidney disease (CHF/CKD) and whether treatment with low-dose erythropoietin stimulating agent (ESA) modulates NGAL levels.. In the EPOCARES trial (ClinTrialsNCT00356733) serum NGAL, hepcidin-25, transferrin saturation (TSAT), reticulocyte hemoglobin content (Ret-He) and endogenous erythropoietin (EPO) levels were measured.. Baseline serum NGAL levels correlated with cystatin C (r=0.767, p<0.001) and baseline EPO levels (r=-0.395, p=0.003). There was no correlation with baseline TSAT, Ret-He, and hepcidin-25 levels. After two weeks, NGAL levels decreased in the ESA-group (p=0.02), while there was no change in the no-ESA group (p=0.62). The magnitude in NGAL decrease in the ESA-group correlated with baseline EPO levels (r=0.431, p=0.01).. In contrast to in HD patients, in combined CKD/ CHF, serum NGAL levels did not correlate with iron metabolism, hence NGAL might reflect tubular damage in these patients. NGAL levels inversely correlated with baseline EPO levels and decreased in response to short-term ESA treatment, which might reflect an effect of ESA on tubular damage. These findings need to be confirmed and alternative explanations should be evaluated.

Topics: Acute-Phase Proteins; Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Erythropoietin; Female; Heart Failure; Hepcidins; Humans; Iron; Lipocalin-2; Lipocalins; Male; Prospective Studies; Proto-Oncogene Proteins; Regression Analysis; Renal Insufficiency, Chronic; Transferrin

No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients.. Patients were randomized (1:1) to receive either 1.2 μg/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-week evaluation period. Two primary end points were assessed: the haemoglobin (Hb) response rate and the change in average Hb concentration between baseline and evaluation.. The Hb response rate for C.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate [95% confidence interval (CI): 89.1, 97.3; P < 0.0001] and comparable with darbepoetin alfa (93.5%; 95% CI: 88.4, 96.8; P < 0.0001). C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similar mean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa [39 patients (25.8%) versus 72 patients (47.7%); P < 0.0001]. Adverse event rates were comparable between the treatment groups.. C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended target range in non-dialysis CKD patients.

Topics: Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Subcutaneous (s.c.) administration of erythropoietin (EPO) is recommended over the intravenous (i.v.) route to reduce doses and costs. Optimal iron treatment is important for the optimal EPO effect. This study investigated whether the haemoglobin (Hb) level of a single patient could be preserved with the same dose of EPO given i.v. as given s.c.. One-hundred and forty-five haemodialysis patients with the same weekly EPO dose s.c. for 3 months and a stable Hb (maximum fluctuation of 1 mmol/l) were randomized in a crossover study to group A (4 months i.v. then 4 months s.c. EPO) or group B (4 months s.c. then 4 months i.v. EPO, with unchanged EPO dose). Ferritin had to be 300-800 μg/l or transferrin saturation ≥ 20%. Patients with a fall in Hb >1 mmol/l were withdrawn.. Ferritin and transferrin saturation remained within the target range, and mean Hb in the range of 1 mmol/l. Mean EPO doses were unchanged in both groups, and no difference was found between the dropouts due to Hb fall >1 mmol/l in the i.v. and s.c. groups during the first period of the trial.. In iron-replete haemodialysis patients the same EPO dose given intravenously is just as effective as given subcutaneously.

Topics: Aged; Anemia; C-Reactive Protein; Cross-Over Studies; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Male; Middle Aged; Parathyroid Hormone; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Statistics, Nonparametric

More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association.. A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4-2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5-2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4-2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results.. The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa-related stroke.. http://www.clinicaltrials.gov. Unique identifier: NCT00093015.

Topics: Aged; Anemia; Case-Control Studies; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Risk Reduction Behavior; Stroke; Treatment Outcome

C.E.R.A., a continuous erythropoietin receptor activator is approved for the treatment of anemia in patients with chronic kidney disease (CKD). The ARCTOS (administration of C.E.R.A. in CKD patients to treat anemia with a twice-monthly schedule) phase 3 study demonstrated the efficacy and safety of C.E.R.A. in correcting anemia when administered once every 2 weeks (Q2W) subcutaneously in patients with CKD not on dialysis. We assessed the feasibility and long-term safety of converting patients who responded to treatment with C.E.R.A. Q2W to C.E.R.A. once every 4 weeks (Q4W) during a 24-week extension period. After the core ARCTOS study period (28 weeks), 296 patients entered the 24-week extension period. At week 29, patients who responded to C.E.R.A. Q2W during the core period were rerandomized to receive subcutaneous C.E.R.A. Q2W or Q4W. Patients in the comparator arm could receive darbepoetin alfa once weekly or Q2W. Dosage was adjusted to maintain hemoglobin (Hb) between 11 and 13 g/dL. Mean Hb levels remained stable in all groups, and were comparable at the end of the extension period (mean [standard deviation], C.E.R.A. Q2W, 11.92 [0.90] g/dL; C.E.R.A. Q4W, 11.70 [0.86] g/dL; darbepoetin alfa, 11.89 [0.98] g/dL). Mean within-patient standard deviation values for Hb were also comparable in all groups (0.66, 0.62, and 0.65 g/dL for C.E.R.A. Q2W, C.E.R.A. Q4W and darbepoetin alfa, respectively). All treatments were well tolerated. Subcutaneous C.E.R.A. Q4W is safe and effective in maintaining stable Hb levels in patients with CKD not on dialysis following correction with subcutaneous C.E.R.A. Q2W.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

To compare the efficacy and safety of epoetin theta and epoetin beta in anaemic patients with chronic kidney disease, undergoing haemodialysis and previously on stable maintenance therapy with epoetin beta.. In this multicentre, randomised, controlled, double-blind study 270 haemodialysis patients were treated intravenously (i.v.) for 24 weeks with either epoetin theta (n = 180) or epoetin beta (n = 90). The primary efficacy endpoint was the change in haemoglobin (Hb) from baseline to end of treatment (efficacy evaluation period, EEP, weeks 15-26). Hb levels, weekly doses of epoetin theta or epoetin beta required to maintain Hb levels, dose changes, safety, tolerability and immunogenicity were evaluated.. EudraCT No. 2005-000143-28.. Mean Hb values were similar in both treatment groups at baseline and during the 24-weeks treatment period. The estimated treatment difference between epoetin theta and epoetin beta from baseline to EEP was -0.01 g/dL (95% confidence interval: -0.24, 0.21), p = 0.9021, indicating that the difference between both groups was not statistically significant. The weekly doses of epoetin theta or epoetin beta required to maintain Hb levels were nearly the same. The changes from baseline to EEP in patients who switched to treatment with epoetin theta (95.5-99.7 IU/kg(BW)) were smaller than in patients staying on their epoetin beta therapy (89.0-98.0 IU/kg(BW)). The profile and the frequency of adverse drug reactions (ADRs) were similar in both treatment groups (21.7% epoetin theta; 22.2% epoetin beta). The most common ADRs were hypertension, headache and arteriovenous fistula thrombosis. None of the patients developed anti-erythropoietin antibodies.. Epoetin theta (i.v.) has a similar efficacy compared to epoetin beta (i.v.) in haemodialysis patients based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was similar in both groups. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes.

Topics: Aged; Aged, 80 and over; Anemia; Combined Modality Therapy; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemodialysis Solutions; Humans; Injections, Intravenous; Male; Middle Aged; Placebos; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

This study assessed plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP) as a prognostic marker of cardiovascular risk in patients with chronic kidney disease stages 3-4 and anaemia treated with epoetin beta to two haemoglobin target ranges.. Of 603 patients enrolled in the Cardiovascular Risk Reduction by Early Anaemia Treatment with Epoetin Beta (CREATE) trial (baseline creatinine clearance 15-35 mL/min; haemoglobin 11.0-12.5 g/dL), 291 were included in this sub-study. Patients received subcutaneous epoetin beta either immediately after randomisation (target 13.0-15.0 g/dL; Group 1), or after their haemoglobin levels had fallen < 10.5 g/dL (target 10.5-11.5 g/dL; Group 2). Chronic heart failure New York Heart Association class III-IV was an exclusion criterion. (ClinicalTrials.gov Identifier: NCT00321919). Cardiovascular event rates were higher in patients with baseline NT-proBNP > 400 vs. ≤ 400 pg/mL (39 vs. 13 events; p = 0.0002). Dialysis was initiated in 68 vs. 42 patients with NT-proBNP > 400 vs. ≤ 400 pg/mL (p = 0.0003). Amongst patients with NT-proBNP > 400 pg/mL, there was no significant difference between treatment groups in risk of cardiovascular events (HR = 0.57; p = 0.08) or time to dialysis (HR = 0.65; p = 0.08). The overall interpretation of this substudy is, however, limited by its relatively small sample size which, together with low clinical event rates, result in a lack of statistical power for some analyses and should be viewed as being hypothesis-generating in nature.. In chronic kidney disease patients with mild-to-moderate anaemia, elevated baseline plasma NT-proBNP levels are associated with a higher risk of cardiovascular events and an accelerated progression towards end-stage renal disease.

Topics: Aged; Anemia; Biomarkers; Cardiovascular Diseases; Comorbidity; Erythropoietin; Female; Humans; Male; Middle Aged; Natriuretic Agents; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Assessment

Partial correction of anemia in patients with chronic kidney disease (CKD) reduces left ventricular hypertrophy (LVH), which is a risk factor for cardiovascular (CV) morbidity, but complete correction of anemia does not improve CV outcomes. Whether LV geometry associates with CV events in patients who are treated to different hemoglobin (Hb) targets is unknown. One of the larger trials to study the effects of complete correction of anemia in stages 3 to 4 CKD was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial. Here, we analyzed echocardiographic data from CREATE to determine the prevalence, dynamics, and prognostic implications of abnormal LV geometry in patients who were treated to different Hb targets. The prevalence of LVH at baseline was 47%, with eccentric LVH more frequent than concentric. During the study, LVH prevalence and mean left ventricular mass index did not change significantly, but LV geometry fluctuated considerably within 2 yr in both groups. CV event-free survival was significantly worse in the presence of concentric LVH and eccentric LVH compared with the absence of LVH (P = 0.0009 and P < or = 0.0001, respectively). Treatment to the higher Hb target associated with reduced event-free survival in the subgroup with eccentric LVH at baseline (P = 0.034). In conclusion, LVH is common and associates with poor outcomes among patients with stages 3 to 4 CKD, although both progression and regression of abnormal LV geometry occur. Complete anemia correction may aggravate the adverse prognosis of eccentric LVH.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Disease-Free Survival; Echocardiography; Erythropoietin; Female; Heart Ventricles; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Renal Insufficiency, Chronic; Stroke

We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin antibodies.. In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions.. We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10x10(9) per liter before treatment to peak counts of greater than 100x10(9) per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period.. This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.).

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Receptors, Erythropoietin; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Assessment of a pharmacist-run anaemia educational programme for patients with chronic renal insufficiency.. Nephrology Department, Grenoble Hospital, France.. A 12-week prospective study, using a before-after intervention design. Included in the study were predialysis outpatients with a haemoglobin level < 10 g/dl, de novo EPO prescription; judged qualified by the nephrologist for self-injections; accepting self-injections. The intervention was a single one-hour individual session between the pharmacist and the patient to target (1) medical and therapeutic information; (2) information on the device, a pen used with a cartridge of beta epoietin; (3) training with the pen; and (4) self-injection of the first dose by the patient, in front of the pharmacist. Main outcome measures were knowledge (7-item questionnaire); handling skills (observation) and Quality of Life (1 Likert scale on apprehension towards self-injections and 3 Linear Analog Scales on energy, daily activities, and general well-being); compliance (self-report on self-administered injections) and haemoglobin level.. Ten patients were followed for 3 months after intervention. The evolution of the knowledge was positive but not statistically significant after the programme (80% of good answers before; 93% 3 months later). Concerning the patients' skills, difficulties with the pen were important at inclusion, (1) to reset the pen into zero position (2.8 tries/patient +/- 1.8); (2) to insert a new cartridge (1.9 +/- 1.1); and (3) to take air out of the cartridge (2.3 +/- 1.2). After the session, results were satisfactory, since 3 months later, all patients were still on self-injections. QoL improved significantly over the study period respectively on energy, daily activities, and general well-being. The mean level of compliance remained above 90% at 3 months for 8 out of 10 patients. Patients reached the haemoglobin target value of 11 g/dl during the second month of treatment.. A tailored educational programme conducted by a pharmacist is beneficial for anaemia patients with chronic renal insufficiency. The programme seems to result in a high level of compliance, leading to an optimal haemoglobin level within two months.

Topics: Adult; Aged; Ambulatory Care; Anemia; Erythropoietin; Female; Follow-Up Studies; France; Health Knowledge, Attitudes, Practice; Hemoglobins; Hospitals, Teaching; Humans; Injections; Male; Middle Aged; Patient Compliance; Patient Education as Topic; Pharmacists; Pharmacy Service, Hospital; Professional Role; Prospective Studies; Quality of Life; Recombinant Proteins; Renal Insufficiency, Chronic; Self Administration

Epoetin delta, unlike recombinant erythropoietins, is produced in a human cell line and therefore has a human-type glycosylation profile.. The pharmacokinetics of epoetin delta were examined in 2 studies in healthy volunteers and 2 studies in patients with chronic kidney disease.. In study 1, 21 healthy men were randomized to receive epoetin delta 15, 40, or 100 IU/kg IV tiw or placebo for 4 weeks. In study 2, an open-label, cross-over study, 32 healthy volunteers were randomized to receive single doses of epoetin delta 75 IU/kg IV or SC. In study 3, 40 patients receiving hemodialysis were withdrawn from epoetin alfa and randomized to receive epoetin delta or epoetin alfa 50 or 100 IU/kg tiw for 4 weeks. Study 4 was a single-dose study comparing epoetin delta 150 and 300 IU/kg IV or SC in 28 hemodialysis patients.. In study 1, after repeated dosing (day 24) in healthy men, mean C(max) values ranged from 219.9 to 1793.0 enzyme-linked immunosorbent assay units (EU)/L; AUC from 827 to 9318 h x EU/L; C1 from 0.014 to 0.024 L/h per kg; Vd from 0.067 to 0.076 L/kg; and t(1/2) from 2.23 to 3.35 hours. There was evidence of a dose-dependent effect of epoetin delta on hemoglobin levels and hematocrit, with doses of 40 and 100 IU/kg associated with significant increases compared with 15 IU/kg (P < 0.001 for dose trend). The only adverse event occurring in > or = 10% of healthy individuals in study 1 was headache (1 [20.0%] in the epoetin delta 15 IU-kg group, 3 [60.0%] in the epoetin delta 100-IU/kg group, 2 [33.3%] in the placebo group). In study 2 in healthy volunteers, mean values for epoetin delta 75 IU/kg IV were 1771 EU/L for C(max), 10,632 h x EU/L for AUC, 0.010 L/h per kg for Cl, 0.074 L/kg for Vd, and 5.12 hours for t(1/2); the corresponding values for epoetin delta 75 IU/kg SC were 113 EU/L, 3231 h x EU/L, 0.035 L/h per kg, 0.760 L/kg, and 14.90 hours. The serum epoetin delta concentration peaked after 10.9 hours with subcutaneous administration. The most common adverse event in study 2 was back pain (10 [31.3%] individuals). In study 3 in patients receiving hemodialysis, mean values for C(max) and AUC with a single dose of epoetin delta 50 IU/kg were 1103 EU/L and 10,896 h x EU/L, respectively, and with the corresponding dose of epoetin alfa were 1354 EU/L and 9957 h x EU/L. Values for the 100-IU/kg doses were approximately double those for the 50-IU/kg doses. Values for Cl, Vd, and t(1/2) were numerically similar for epoetin delta and epoietin alfa across doses. Epoetin delta 100 IU/kg was associated with a numerically greater rate of increase in hemoglobin compared with the 50-IU/kg dose (mean, 0.025 vs -0.004, respectively); the results were similar for epoetin alfa (0.029 vs -0.001). The difference between epoetin alfa and epoetin delta was not statistically significant. The most common adverse events were related to edema (peripheral edema: 60%/50% for epoetin delta 50/100 IU/kg and 60%/60% for epoetin alfa 50/100 IU/kg; facial edema: 30%/30% and 50%/70%, respectively; generalized edema: 50%/30% and 40%/40%). In study 4 in patients receiving hemodialysis, mean C(max) values with epoetin delta 150 and 300 IU/kg IV were 3257 and 4770 EU/L, respectively; the corresponding mean values were 36,208 and 77,736 h x EU/L for AUC, 0.007 and 0.005 L/h per kg for Cl; 0.0. These studies in healthy volunteers and patients with chronic kidney disease indicate that the pharmacokinetics of epoetin delta are dose dependent but nonlinear, leading to dose-dependent increases in hemoglobin levels. The pharmacodynamic response to epoetin delta appeared to be as expected for an epoetin.

Topics: Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Routes; Erythropoietin; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established.. We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.. During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1.. In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 [ClinicalTrials.gov].).

Topics: Anemia; Cardiovascular Diseases; Disease Progression; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Survival Analysis

Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined.. In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke.. A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event.. The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].).

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hematinics; Hemoglobins; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Renal Insufficiency, Chronic; Stroke; Survival Analysis

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Hypoxia; Renal Insufficiency, Chronic

The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305).. ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study).. In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined.. Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat.. The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

Topics: Darbepoetin alfa; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Animals; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Indican; Mice; Renal Insufficiency, Chronic

Anemia in patients with chronic kidney disease (p-CKDs) may initiate or exacerbate left ventricular hypertrophy (LVH). This study aimed to determine whether treatment using long-acting erythropoietin-stimulating agents (L-ESAs) is independently associated with LVH during the pre-dialysis to maintenance dialysis period in p-CKDs.. Physical and laboratory examinations were performed 120 days before initiating dialysis in p-CKDs (baseline). To evaluate the left ventricular mass index (LVMI) after starting dialysis, the mean hemoglobin (Hb) was defined as the average at the start of dialysis and 6 months after starting dialysis. Changes in the LVMI were observed in three groups according to mean Hb levels (Hb < 10.1, 10.1 < Hb < 11.0, and Hb > 11.0 g/dL for Groups 1, 2, and 3, respectively). LVMI was evaluated using echocardiography at the pre-dialysis, initiation, and maintenance dialysis periods.. A lower LVMI at dialysis initiation and an improvement in LVMI were detected in the highest tertile group of mean Hb (11.0 g/dl). Consequently, in the high Hb group (Hb level > 11.0 g/dl), LVMI remained low from dialysis initiation until after 6 months.The relationship between Hb and LVMI was not significant; however, a constant correlation with β ≥ 0.4 in the absolute value was maintained.. L-ESAs may correlate with Hb and LVMI after administration, independent of the baseline LVMI and Hb values. These findings have therapeutic implications in the treatment strategies for p-CKDs during the pre-dialysis to maintenance dialysis period.

Topics: Anemia; Dialysis; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Longitudinal Studies; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies

This study was conducted to evaluate whether the efficacy and safety profile of recombinant human erythropoietin (rhEPO) manufactured by Daewoong Pharmaceutical Co., Ltd was similar to biological products approved by the drug safety regulatory authority.. It was an open-label, randomized, comparative, parallel, multi-center study in hemodialysis patients with anemia. The reference product at an individualized dose 3 times a week was given in 4-8 weeks of titration period and hemoglobin (Hb) level was controlled to reach the range of 10-12 g/dL. Then, the subjects were randomly administered with reference or test product with the same dose regimen. The primary endpoints were to demonstrate the Hb level change between baseline and evaluation period in both treatment groups, while the secondary endpoints were the mean change in weekly dosage per kg body weight and the instability rate of Hb level during maintenance and evaluation period. The safety was evaluated based on the adverse events incidence.. There was no statistical difference in the change of Hb between test and reference (0.14 g/dL and 0.75 g/dL respectively, with p>0.05), also for the mean changes of weekly dosage between groups (1091.40 IU and 570.15 IU respectively, with p>0.05). The instability rate of Hb in both test and reference was not statistically significantly different as well (26 and 15% respectively, with p>0.05).. This study proves that the efficacy indicated by the change instability of Hb and safety indicated by adverse event incidence of Epodion and the reference product on chronic kidney disease were similar.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Insufficiency, Chronic; Treatment Outcome

Anemia is a common complication of systemic inflammation. Proinflammatory cytokines both decrease erythroblast sensitivity to erythropoietin (EPO) and increase the levels of the hepatic hormone hepcidin, sequestering iron in stores and causing functional iron deficiency. Anemia of chronic kidney disease (CKD) is a peculiar form of anemia of inflammation, characterized by impaired EPO production paralleling progressive kidney damage. Traditional therapy based on increased EPO (often in combination with iron) may have off-target effects due to EPO interaction with its non-erythroid receptors. Transferrin Receptor 2 (Tfr2) is a mediator of the iron-erythropoiesis crosstalk. Its deletion in the liver hampers hepcidin production, increasing iron absorption, whereas its deletion in the hematopoietic compartment increases erythroid EPO sensitivity and red blood cell production. Here, we show that selective hematopoietic Tfr2 deletion ameliorates anemia in mice with sterile inflammation in the presence of normal kidney function, promoting EPO responsiveness and erythropoiesis without increasing serum EPO levels. In mice with CKD, characterized by absolute rather than functional iron deficiency, Tfr2 hematopoietic deletion had a similar effect on erythropoiesis but anemia improvement was transient because of limited iron availability. Also, increasing iron levels by downregulating only hepatic Tfr2 had a minor effect on anemia. However, simultaneous deletion of hematopoietic and hepatic Tfr2, stimulating erythropoiesis and increased iron supply, was sufficient to ameliorate anemia for the entire protocol. Thus, our results suggest that combined targeting of hematopoietic and hepatic Tfr2 may be a therapeutic option to balance erythropoiesis stimulation and iron increase, without affecting EPO levels.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Hepcidins; Inflammation; Iron; Iron Deficiencies; Mice; Receptors, Transferrin; Renal Insufficiency, Chronic

Topics: Erythropoietin; Gastric Antral Vascular Ectasia; Gastrointestinal Hemorrhage; Humans; Renal Insufficiency, Chronic

Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor β-induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Creatinine; Endothelial Cells; Erythropoietin; Mice; Proto-Oncogene Proteins c-akt; Renal Insufficiency, Chronic; Vascular Endothelial Growth Factor A

Both insufficient kidney production of erythropoietin and inflammation-mediated reduction of transferrin-bound iron are major factors in anemia of chronic kidney disease. Improved therapies for anemia in chronic kidney disease may involve modifying regulators of erythropoiesis and iron availability. Olivari et al. show in a mouse model of chronic kidney disease that transferrin receptor 2 in hepatocytes, where it is required for hepcidin production, and in erythroid cells, where it downregulates erythropoietin receptor activity, is a potential therapeutic target.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hepcidins; Iron; Mice; Receptors, Transferrin; Renal Insufficiency, Chronic

Hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) is a novel agent for the treatment of renal anemia. HIF-PHI increases endogenous erythropoietin production by inhibiting the degradation of an erythropoietin transcription factor. Although beneficial effects are expected from HIF-PHI, its novel mechanism raises concerns regarding the risk of potential adverse events. The cases of hypothyroidism, which had not been reported in clinical trials, were reported after the administration of roxadustat in a real-world setting. However, the effects of HIF-PHIs on thyroid function have not yet been fully evaluated. This study aimed to assess the clinical impact of HIF-PHIs on thyroid function using the Japanese Adverse Drug Event Report database, a spontaneous reporting system in Japan, because HIF-PHIs were made available in Japan before they were available in other countries. Although a disproportionality signal for hypothyroidism was detected with roxadustat (reporting odds ratio [ROR]:22.1, 95% confidence interval [CI]:18.3-26.7, no signals were detected with another HIF-PHI, daprodustat (ROR:1.3, 95%CI:0.3-5.4), and epoetin beta pegol (ROR:1.2, 95%CI:0.5-2.7). Signals of hypothyroidism due to roxadustat were also detected regardless of age or sex. Approximately 50% of hypothyroidism cases were reported within 50 days of starting roxadustat use. These results indicate that roxadustat use may be related to the development of hypothyroidism. The need for monitoring of thyroid function should be alerted during roxadustat administration regardless of age or sex.

Topics: Drug-Related Side Effects and Adverse Reactions; East Asian People; Erythropoietin; Humans; Hypothyroidism; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Renal Insufficiency, Chronic

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using

Topics: Animals; Disease Models, Animal; Erythropoietin; Fibrosis; Humans; Indican; Inflammation; Kidney; Mice; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Sulfotransferases; Ureteral Obstruction

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) are a new drug class for the treatment of renal anemia. HIF-PHI increase the expression of genes such as erythropoietin and genes involved in iron homeostasis. HIF-PHI were found to be superior to placebo in increasing hemoglobin levels and non-inferior to erythropoiesis stimulating agents (ESA). Furthermore, HIF-PHI appeared to positively influence iron parameters and also appeared to be effective in patients with elevated inflammatory values. The cardiovascular safety of HIF-PHI was found to be similar to ESA in most studies. However, a stronger risk of deep vein thrombosis and thrombosis of the shunt was found with treatment of HIF-PHI compared to ESA. HIF-PHI can be considered as an alternative to ESA, with the positive effect on iron homeostasis, the oral administration and the potential possibility to treat patients with ESA hyporesponsiveness as additional benefits, although effectiveness in this subgroup has yet to be demonstrated.

Topics: Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Topics: Acute Kidney Injury; Biomarkers; Critical Care; Erythropoietin; Fibroblast Growth Factor-23; Humans; Prospective Studies; Renal Insufficiency, Chronic; Sepsis

Serum creatinine (SCr) is a routine marker of kidney injury but also increases with dehydration and muscular work. This study was to elucidate whether increase in SCr is associated with more specific markers of kidney tubular and interstitial injury and function, during prolonged heat stress among workers at high risk of chronic kidney disease of non-traditional origin (CKDnt).. Urine monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), calbindin, glutathione S-transferase-π (GST-π), clusterin, interleukin 18 and albumin, fractional excretion of potassium (FEK), blood haemoglobin, serum potassium, ferritin and erythropoietin were measured before and after harvest in a sample of 30 workers with a ≥0.3 mg/dL SCr increase across harvest (cases), and 53 workers with stable SCr (controls).. Urine MCP-1 (p for differential cross-harvest trend <0.001), KIM-1 (p=0.002), calbindin (p=0.02), GST-π (p=0.04), albumin (p=0.001) and FEK (p<0.001) increased in cases, whereas blood haemoglobin (p<0.001) and serum erythropoietin (p<0.001) decreased.. Several markers of tubular and interstitial injury and function changed as SCr increased across a harvest season, supporting the use of SCr as an indicator of kidney injury in physically active workers regularly exposed to heat stress. Repeated injury similar to that described here, and continued work under strenuous and hot conditions with similarly elevated injury markers is likely to worsen and possibly initiate CKDnt.

Topics: Acute Kidney Injury; Albumins; Biomarkers; Calbindins; Creatinine; Erythropoietin; Female; Heat Stress Disorders; Humans; Kidney; Male; Potassium; Renal Insufficiency, Chronic; Saccharum

Fibroblast-like renal erythropoietin (Epo) producing (REP) cells of the corticomedullary border region "sense" a decrease in blood oxygen content following anaemia or hypoxaemia. Burst-like transcription of Epo during tissue hypoxia is transient and is lost during fibrotic tissue remodelling, as observed in chronic kidney disease. The reason for this loss of Epo expression is under debate. Therefore, we tested the hypothesis that REP cell migration, loss and/or differentiation may cause Epo inhibition.. Using a reporter mouse that allows permanent labelling of active REP cells at any given time point, we analysed the spatiotemporal fate of REP cells following their initial hypoxic recruitment in models of hypoxaemia and renal tissue remodelling.. In long-term tracing experiments, tagged REP reporter cells neither died, proliferated, migrated nor transdifferentiated into myofibroblasts. Approximately 60% of tagged cells re-expressed Epo upon a second hypoxic stimulus. In an unilateral model of tissue remodelling, tagged cells proliferated and ceased to produce Epo before a detectable increase in myofibroblast markers. Treatment with a hypoxia-inducible factor (HIF) stabilizing agent (FG-4592/roxadustat) re-induced Epo expression in the previously active REP cells of the damaged kidney to a similar extent as in the contralateral healthy kidney.. Rather than cell death or differentiation, these results suggest cell-intrinsic transient inhibition of Epo transcription: following long-term dormancy, REP cells can repeatedly be recruited by tissue hypoxia, and during myofibrotic tissue remodelling, dormant REP cells are efficiently rescued by a pharmaceutic HIF stabilizer, demonstrating persistent REP cell functionality even during phases of Epo suppression.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoietin; Hypoxia; Kidney; Mice; Renal Insufficiency, Chronic

Renal anemia is a frequently encountered complication in patients suffering from advanced chronic kidney disease. This is mainly due to the decreased secretion of erythropoietin by the diseased kidneys. The current treatment of renal anemia is based on iron substitution and administration of recombinant erythropoietin. The discovery of HIF (Hypoxia-Inducible Factor) has led to the development of a new class of molecules that block the activity of prolyl-4-hydroxylases and stabilize HIF (Hypoxia-Inducible Factor), a transcription factor that plays an essential role in numerous cellular pathways, including those linked to erythropoiesis and iron metabolism. In this article, we discuss the current understanding of the pathophysiological mechanisms underlying renal anemia and the potential role of the new HIF-stabilizers in its treatment.. L’anémie rénale est un problème courant chez les patients souffrant d’insuffisance rénale chronique avancée. Elle est due essentiellement à la diminution de la sécrétion d’érythropoïétine par les reins malades. Le traitement actuel de l’anémie rénale repose sur la substitution martiale et l’administration d’érythropoïétine recombinante. Récemment, une nouvelle classe de molécules a été développée, dont l’effet repose sur l’inactivation des prolyl-4-hydroxylases, qui dégradent normalement l’HIF (Hypoxia- Inducible Factor), un facteur de transcription important dans l’expression des gènes liés à l’érythropoïèse et au métabolisme du fer. Dans cet article, nous ferons le point sur les connaissances actuelles de la pathophysiologie de l’anémie rénale et le rôle potentiel des inhibiteurs des prolyl-4-hydroxylases dans son traitement.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Renal Insufficiency, Chronic

We have previously demonstrated that the Na-K-ATPase signaling-mediated oxidant amplification loop contributes to experimental uremic cardiomyopathy and anemia induced by 5/6th partial nephrectomy (PNx). This process can be ameliorated by systemic administration of the peptide pNaKtide, which was designed to block this oxidant amplification loop. The present study demonstrated that the PNx-induced anemia is characterized by marked decreases in red blood cell (RBC) survival as assessed by biotinylated RBC clearance and eryptosis as assessed by annexin V binding. No significant change in iron homeostasis was observed. Examination of plasma samples demonstrated that PNx induced significant increases in systemic oxidant stress as assessed by protein carbonylation, plasma erythropoietin concentration, and blood urea nitrogen. Systemic administration of pNaKtide, but not NaKtide (pNaKtide without the TAT leader sequence) and a scramble "pNaKtide" (sc-pNaKtide), led to the normalization of hematocrit, RBC survival, and plasma protein carbonylation. Administration of the three peptides had no significant effect on PNx-induced increases in plasma erythropoietin and blood urea nitrogen without notable changes in iron metabolism. These data indicate that blockage of the Na-K-ATPase signaling-mediated oxidant amplification loop ameliorates the anemia of experimental renal failure by increasing RBC survival.

Topics: Anemia; Animals; Erythrocytes; Erythropoietin; Female; Half-Life; Humans; Iron; Male; Mice; Mice, Inbred C57BL; Nephrectomy; Oxidants; Peptides; Renal Insufficiency, Chronic; Sodium-Potassium-Exchanging ATPase

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Mixed Function Oxygenases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Topics: Anemia; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia in patients with chronic kidney disease (CKD) is the result of reduced erythropoietin, disturbed erythropoiesis and decreased lifespan of circulating erythrocytes. Excessive eryptosis or premature suicidal erythrocyte death is characterized by cell shrinkage and phosphatidylserine externalization. This study aimed to explore accelerated eryptosis and accompanying biochemical alterations in CKD patients.. A total of 106 CKD patients (59 predialysis [PreD] patients, 26 haemodialysis [HD] patients and 21 peritoneal dialysis [PD] patients) and a control group composed of 29 healthy volunteers were included in this study. Data on superoxide dismutase (SOD) activity (U/mL), annexin-V binding (mean fluorescent intensity, MFI) and intracellular calcium ([Ca. In conclusion, our findings revealed the presence accelerated eryptosis, as a potential contributing factor to development of anemia, in patients with CKD stages 3-5D. Inflamation and parathormon can also accelerate eryptosis. Favorable effect of CCB and EPO on eryptosis needs to be confirmed in larger scale studies.

Topics: Albumins; Anemia; Annexin A5; Calcium; Calcium Channel Blockers; Eryptosis; Erythropoietin; Ferritins; Humans; Phosphatidylserines; Renal Insufficiency, Chronic; Superoxide Dismutase

Erythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis.. We investigated Epo transcription in myofibroblasts and characterized the histological distribution of kidney Epo transcripts by RNA in situ hybridization combined with immunofluorescence in mice with adenine nephropathy (AN) treated with HIF-PHI molidustat.  Lectin absorption chromatography was used to assess liver-derived EPO.  In addition, we examined kidney Epo transcription in Phd2 knockout mice with obstructive nephropathy.. In AN, molidustat-induced Epo transcripts were not found in areas of fibrosis and did not colocalize with interstitial cells that expressed α-smooth muscle actin, a marker of myofibroblast transdifferentiation. Epo transcription was associated with megalin-expressing, kidney injury molecule 1-negative nephron segments and contingent on residual renal function. Liver-derived EPO did not contribute to serum EPO in molidustat-treated mice. Epo transcription was not associated with myofibroblasts in Phd2 knockout mice with obstructive nephropathy.. Our studies suggest that HIF-PHIs do not reactivate Epo transcription in interstitial myofibroblasts and that their efficacy in inducing kidney EPO in CKD is dependent on the degree of myofibroblast formation, the preservation of renal parenchyma and the level of residual renal function.

Topics: Animals; Cell Transdifferentiation; Erythropoietin; Fibrosis; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Mice; Mice, Knockout; Myofibroblasts; Nephrons; Prolyl Hydroxylases; Renal Insufficiency, Chronic

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been highlighted as a potential risk factor for cardiovascular disease in patients with chronic kidney disease (CKD).. We assessed cross-sectionally the prevalence, associated factors, and treatment status of anemia and ESA hyporesponsiveness in 4460 non-dialysis-dependent CKD patients enrolled in a multicenter cohort in Japan. Anemia was defined as a hemoglobin (Hb) level of less than 11 g/dL or receiving ESA therapy. ESA hyporesponsiveness was defined by the erythropoietin-resistance index (ERI), which was the erythropoietin dose per week divided by body weight and Hb level (U/kg/week/g/dl).. Of the 4460 patients, 1050 (23.5%) had anemia. ESAs were administered to 626 patients, reaching a percentage of 57.5% of patients with stage G5 CKD. However, the ESA treatment rate was only 49.0% in patients with a hemoglobin level of < 11 g/dL. The proportion of patients receiving iron supplementation was lower than that of patients receiving ESAs regardless of CKD stage or hemoglobin level, and a significant proportion of patients did not receive iron supplementation, even those with iron deficiency. The ERI increased with CKD stage progression, and the multiple regression analysis showed that age, female sex, body mass index, cholesterol, glomerular filtration rate, and intact parathyroid hormone level were independent contributors.. Our findings demonstrate that many Japanese patients with non-dialysis-dependent CKD receiving ESAs fail to maintain adequate hemoglobin levels. These results suggest the need for interventions for ESA hyporesponsiveness factors in addition to iron supplementation.

Topics: Anemia; Cross-Sectional Studies; Drug Tolerance; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iron; Japan; Prevalence; Renal Insufficiency, Chronic

Although patients with either β-thalassemia or chronic kidney disease (CKD) clinically correlate with severe osteoporosis, the mechanism by which CKD exposed to high phosphate affects bone turnover has not been characterized in β-thalassemia. We aimed to determine the effects of renal insufficiency on high phosphate intake induced changes in bone metabolism after 5/6th nephrectomy in hemizygous β-globin knockout (BKO) mice. Male BKO mice manifested severe anemia and osteopenia. Nephrectomy induced renal fibrosis and reduced renal function as assessed by increased serum urea nitrogen levels. Moreover, nephrectomy increased bone turnover leading to bone loss in wild type (WT) but not BKO mice. In nephrectomized BKO, PBS in drinking water induced hyperphosphatemia, and hypercalcemia along with osteopenia in both cancellous and cortical bone. Histomorphometric analysis confirmed reduced cancellous bone volume due to decreased bone formation rate, osteoblast number and osteoclast number. The mRNA levels for Alpl, Sp7, Kl, Tnfsf11, and Tnfsf11/Tnfrsf11b were decreased in nephrectomized BKO mice drinking PBS. Interestingly, Fgf23, a bone-derived hormone produced by osteocytes and osteoblasts in response to hyperphosphatemia, were remarkably increased in nephrectomized BKO mice following PBS intake. Serum FGF23 and erythropoietin levels were markedly elevated in BKO mice. Nephrectomy decreased serum erythropoietin but not FGF23 levels. Hyperphosphatemia in BKO mice increased serum erythropoietin, FGF23, and PTH levels, nominating these factors as candidate mediators of bone loss in thalassemic mice with CKD during phosphate retention.

Topics: Animals; beta-Thalassemia; Bone Diseases, Metabolic; Erythropoietin; Fibroblast Growth Factors; Humans; Hyperphosphatemia; Male; Mice; Phosphates; Renal Insufficiency, Chronic

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

Topics: Anemia; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Ferritins; Glycine; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Picolinic Acids; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Transferrins

Topics: Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Prolyl-Hydroxylase Inhibitors; Pyrazoles; Renal Insufficiency, Chronic; Triazoles

Topics: Anemia; Erythropoietin; Hematinics; Humans; Renal Insufficiency, Chronic; Uncertainty

Anemia due to chronic kidney disease (CKD) is often associated with decreased erythropoietin (EPO) levels in the blood. Treatments available are improving blood iron levels and administration of exogenous EPO (rhEPO). This study aims to assess the safety and immunogenicity of Epodion, a biosimilar rhEPO product, in haemodialysis patients with CKD-associated anaemia in three Indonesian hospitals.. This prospective, open label, single arm, and multicenter study enrolled patients with anemia associated with CKD under hemodialysis treatment. Patient eligibility was assessed within the 4-week screening period. Blood samples for determination of erythropoietin antibody (Anti-Drug Antibody) were taken at week-0, 24, and 52 using a validated and highly sensitive bridging ELISA method. Evaluation of Neutralizing Antibody (NAb) was carried out to confirm the impact of the antibody to pharmacological activity (e.g., antibody-mediated PRCA) when the ADA detection of patients was positive after screening and confirmatory assay.. Results from all tested patients show that Epodion could maintain hemoglobin and hematocrit levels. ADA detection using ELISA assay yielded negative results for all plasma samples of week-24 and week-52, so the evaluation of NAb was not carried out. No adverse events were considered relevant to tested product.. This study proves no immunogenic effect of Epodion on stimulating immune system's antibodies in Indonesian patients with CKD-associated anemia.

Topics: Anemia; Antibodies, Neutralizing; Biosimilar Pharmaceuticals; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Iron; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in <30% of anemic HF patients. Erythropoiesis stimulating agents (ESAs) improve symptoms but are associated with increased risk of thromboembolic events in anemic HF patients with CKD. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia. These agents work by stabilizing the HIF complex, thereby stimulating endogenous erythropoietin production. We hypothesized that HIF-PH inhibitors may be associated with reduced risk of cardiovascular outcomes compared with ESAs in anemic HF patients with CKD. Accordingly, we aim to perform the meta-analysis of studies on the efficacy and safety of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD.. This meta-analysis will include prospective cohort studies and randomized controlled trials on the effect of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be cardiovascular death. The secondary outcomes will be all-cause death, hospitalization for HF, HF symptoms, exercise capacity, health-related quality of life, and hemoglobin levels.. This meta-analysis will evaluate the effect of HIF-PH inhibitors in anemic HF patients with CKD, providing evidence regarding the use of HIF-PH inhibitors in these patients.. INPLASY202230103.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Meta-Analysis as Topic; Prolyl-Hydroxylase Inhibitors; Prospective Studies; Quality of Life; Renal Insufficiency, Chronic; Systematic Reviews as Topic

Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD).. Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported.. Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa.. In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

Topics: Anemia; Clinical Trials, Phase III as Topic; Epoetin Alfa; Erythropoietin; Ferritins; Glycine; Hemoglobins; Hepcidins; Humans; Iron; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Anaemia is a very common complication of chronic kidney disease (CKD) and renal failure. The view of the treatment of anaemia has changed considerably since the introduction of ESAs (erythropoiesis-stimulating agents) into clinical practice, and the safety of this treatment is now prioritised over complete normalisation of haemoglobin (Hb) values. Iron administration is the mainstay of treatment in this group of patients, with intravenous administration proving to be both more effective and safer in both predialysis and dialysis patients. In addition to the long-used ESAs, a number of new agents developed to favourably influence erythropoiesis have recently been tested for the correction of anaemia. Among those with the greatest potential are the HIF-stabilizers (roxadustat, molidustat, vadadustat and daprodustat), which act through stimulation of erythropoiesis genes and thus represent a novel mechanism of action in the treatment of anaemia. In phase 3 clinical trials, these agents have shown the same efficacy in increasing Hb levels as ESAs, but much emphasis has recently been placed on their safety profile. They are orally administered agents and some of them are already approved and used in clinical practice. The first of these, roxadustat, is currently reimbursed also in the Czech Republic. Other molecules affecting anaemia, such as sotatercept, have also been confirmed to be effective in phase 1 and 2 clinical trials and are awaiting results from larger randomised trials.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia is a common complication of chronic kidney disease (CKD). The insufficient erythropoietin (EPO) production by the kidneys and iron deficiency are the main causes. Iron supplementation and the administration of recombinant EPO are the main treatment modalities. New iron formulations that can be administered orally, intravenously or directly via the dialysate have recently been developed to improve efficacy and tolerance. Ferric citrate administered orally can effectively corrects anemia in case of iron deficiency and in addition chelate phosphate in the gut lumen. Ferric carboxymaltose allows intravenous administration of larger doses given less frequently. Ferric pyrophosphate citrate administered directly via the dialysate allows the compensation of iron losses during the hemodialysis session. HIF-prolyl-hydroxylase inhibitors are a new therapeutic class of erythropoiesis-stimulating agents. Orally administered, they act by stabilizing the HIF transcription factor involved in the initiation of erythropoietin production by hypoxia. Several clinical studies have recently evaluated these new molecules in comparison with recombinant EPO. In CKD patients not yet on dialysis or undergoing dialysis therapy non-inferiority in correcting anemia has been demonstrated compared with recombinant EPO. The decrease in circulating hepcidin they induce appears greater than that induced by injectable recombinant EPO. Presently available reports on the safety of HIF-prolyl-hydroxylase inhibitors are reassuring but need to be confirmed in longer-term studies of larger size. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.

Topics: Anemia; Dialysis Solutions; Erythropoietin; Humans; Iron; Iron Deficiencies; Kidney; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Chronic renal failure are caused by impaired kidney function; this organ is essential in the metabolism, filtration, and excretion of compounds. Human hepatitis B virus is common in dialysis patients with chronic renal failure, and chronic kidney disease (CKD) is also associated with anemia in dialysis patients. In this study, 50 (36 men and 14 women) dialysis patients from Imamian Al-Khademian city, with ages between 30 and 77 years, and a healthy group (control group) with ages ranging between 30 and 62 years, were evaluated. Detection of hepatitis B virus by a molecular technique of real-time PCR and the concentration of erythropoietin hormone detected by the ELISA technique. The results showed that the prevalence of dialysis patients aged 41-50 and 60-51 was 20% and 18%, respectively. The detection of Hepatitis B from the serum of dialysis patients' samples showed that HBV was seen in 15 (30%) of the 50 serum samples. The concentration of the erythropoietin hormone in dialysis patients' samples was lower than in the healthy groups (a control group). Also, the concentration of erythropoietin hormone was significantly lower in dialysis patients compared with the control group (

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hepatitis B; Humans; Iraq; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic

Oxygen biology is currently a focus of intensive scientific research. Three scientists received the Nobel prize in physiology or medicine for their outstanding scientific efforts in revealing the mechanisms of oxygen sensing and defense against hypoxia. Hypoxia is a final common pathway to end-stage kidney disease and plays a crucial role in the pathogenesis of cardiovascular complications. Hypoxia-inducible factors (HIFs) are master regulators of defensive mechanisms against hypoxia. Erythropoietin is one of the main targets of HIFs that enhances oxygen delivery by increasing the production of red blood cells. HIF levels are regulated by HIF-prolyl hydroxylase (HIF-PH) inhibitors, which are now available as a new therapeutic modality against anemia in chronic kidney disease. HIF-PH inhibitors raise some theoretical concerns, but should be noted for their potential organ-protective effects.

Topics: Anemia; Erythropoietin; Humans; Hypoxia; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

This study investigated whether administering erythropoiesis-stimulating agents (ESAs) improves endothelial function in patients with non-dialysis chronic kidney disease (CKD) and anemia.. This single-center, prospective, single-arm comparison study enrolled patients with non-dialysis CKD (stages 4-5) and hemoglobin levels <10 g/dL. ESA administration followed the Kidney Disease: Improving Global Outcomes guideline. The primary endpoint was the change in flow-mediated dilatation after ESA administration in individual patients. The secondary endpoints were changes in 6-minute walk test results, blood pressure, New York Heart Association class, and echocardiographic parameters. The echocardiographic parameters examined included chamber quantification, Doppler parameters, and systolic and diastolic function parameters.. Initially, 13 patients were screened, but 2 discontinued due to either heart failure or voluntary withdrawal. The mean flow-mediated dilatation values significantly increased by 10.59% (from 1.36% ± 1.91% to 11.95% ± 8.11%, P = .001). Echocardiographic findings showed that the left ventricular mass index decreased by 11.9 g/m2 (from 105.8 ± 16.3 to 93.9 ± 19.5 g/m2, P  =  .006), and the left atrial volume index decreased by 10.8 mL/m2 (from 50.1 ± 11.3 to 39.3 ± 11.3 mL/m2, P = .004) after 12 weeks of ESA administration. There were no significant differences between pre- and post-ESA treatment 6-minute walk test results. No significant side effects were observed during the study period.. This is the first clinical study to demonstrate that an ESA improves endothelial dysfunction, left ventricular hypertrophy, and left atrial volume in patients with non-dialysis CKD. Thus, ESAs may be considered as adjunctive therapy for reducing cardiovascular risk in these patients.

Topics: Aged; Anemia; Blood Pressure; Comorbidity; Echocardiography; Endothelium, Vascular; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Renal Insufficiency, Chronic; Severity of Illness Index; Walk Test

To compare the effectiveness of erythropoietin alpha and erythropoietin beta in anemia management in the hemodialysis population.. Quasi-experimental study.. Department of Nephrology, The Kidney Center Postgraduate Training Institute (TKC-PGTI), Karachi, from December 2019 to July 2020.. All participants were initially started on erythropoietin alpha and then converted to erythropoietin beta after three months. The effectiveness of the erythropoietin alpha and erythropoietin beta was calculated on the basis of net change of mean hemoglobin and mean hematocrit level in the last four weeks on either erythropoietin therapy.. A total of 80 patients completed the study, in which 47 (58.8%) were males while 33 (41.3%) were females. The mean age was 59.7 ± 14.7 years. The net mean hemoglobin change during last 04 weeks was  ̶ 0.19 ± 1.2 and  ̶ 0.03 ± 1.0 for erythropoietin alpha and erythropoietin erythropoietin beta, respectively (p = 0.41). The net mean hematocrit change during the last four weeks was  ̶ 0.45 ± 3.9 and  ̶ 0.49 ± 3.7 for erythropoietin alpha and erythropoietin beta, respectively (p = 0.95). The mean weekly erythropoietin dosage per Kg body weight during the last four weeks was 177.6 ± 130.4 IU/Kg/week for erythropoietin alpha and 121.3 ± 69.6 IU/Kg/week for erythropoietin beta (p = <0.001).. Erythropoietin alpha and erythropoietin beta have similar therapeutic efficacy in anemia management in chronic kidney disease patients. Reduced dosage of erythropoietin beta achieves and maintains the target hemoglobin level. Key Words: Efficacy, Erythropoietin, Anemia, Chronic kidney disease.

Topics: Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

The most important contributors to the anemia of patients with chronic kidney disease are insufficient erythropoietin production and erythropoietin hyporesponsiveness, decreased red blood cell half-life, iron deficiency, and inflammation. However, in contrast to the role of kidney failure, that of proteinuria and nephrotic syndrome is less clear. Bissinger et al. now provide evidence in mouse models and patients with chronic kidney disease that heavy proteinuria alters erythrocyte metabolism and increases erythrocyte death.

Topics: Anemia; Animals; Erythropoietin; Humans; Mice; Nephrotic Syndrome; Proteinuria; Renal Insufficiency, Chronic

Topics: Adolescent; Adult; Anemia; Cohort Studies; Erythropoietin; Female; Humans; Pregnancy; Pregnancy Complications, Hematologic; Renal Insufficiency, Chronic

Topics: Anemia; Epoetin Alfa; Erythropoietin; Humans; Network Meta-Analysis; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Epoetin Alfa; Erythropoietin; Humans; Network Meta-Analysis; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic

Iron metabolism, hepcidin and some blood profiles were investigated in 13 healthy and 31 chronic kidney disease (CKD) dogs. The study consisted of 2 experiments, experiment I included healthy dogs (CONT) and CKD dogs (stage 2, 3 and 4), while experiment II consisted of anemic CKD dogs subjected to 28-day darbepoetin alfa treatment. The response to darbepoetin alfa could divide anemic CKD dogs into responder (RP) and non-responder (NRP) subgroups. The results from experiment I showed that packed cell volume (PCV) and plasma albumin concentration were significantly lower in CKD dogs of all stages while the total iron binding capacity (TIBC) was lower in only CKD stage 3 and 4 compared with dogs in CONT group. The PCV was related to both TIBC and albumin when considering among all dogs or only in CKD dogs. The hepcidin concentration in CKD dogs with anemia was lower than those without anemia (P<0.05). In experiment II before darbepoetin alfa treatment, RP subgroup had significantly higher iron and TIBC compared with NRP subgroup (P<0.05), the iron concentration was decreased only in RP subgroup after darbepoetin alfa treatment (P<0.05). The percent increase in PCV was correlated with initial TIBC (P<0.01). Plasma hepcidin concentration was not different between CONT and CKD groups and between RP and NRP subgroups both before and after darbepoetin alfa treatment. It is concluded that TIBC and plasma iron concentration play role on anemia and erythropoietic response to darbepoetin alfa treatment in CKD dogs.

Topics: Animals; Darbepoetin alfa; Dog Diseases; Dogs; Erythropoiesis; Erythropoietin; Hemoglobins; Iron; Renal Insufficiency, Chronic

Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies.

Topics: Anemia; Animals; Erythropoietin; Fibroblast Growth Factor-23; Glycine; Hepcidins; Humans; Kidney; Mice; Mice, Knockout; Picolinic Acids; Renal Insufficiency, Chronic

Decreased erythropoietin levels and impaired iron metabolism due to excessive hepcidin levels are responsible for renal anaemia in patients undergoing haemodialysis. Recently, erythroferrone (ERFE) has been identified as a factor that regulates hepcidin. In addition, fibroblast growth factor 23 (FGF23), which has been recognized as a phosphorus-regulating hormone, appears to be involved in haematopoietic regulation. Clarification of the detailed mechanism of haematopoiesis could lead to the improvement of renal anaemia treatment.. Epoetin beta pegol (CERA) was administered to patients undergoing haemodialysis at week 0, and the same amount of CERA with saccharated ferric oxide (SFO) was administered at week 4. The changes in haematopoiesis-related biomarkers, including ERFE, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), and inflammatory markers, were examined.. Administration of CERA increased ERFE levels, decreased hepcidin levels, and stimulated iron usage for haematopoiesis, leading to an increase in reticulocytes (Ret) and haemoglobin (Hb). Simultaneous administration of SFO with CERA (CERA + SFO) significantly attenuated the responses of ERFE, Ret, and Hb compared with CERA alone. Although iFGF23 levels were not affected by either CERA or CERA + SFO, cFGF23 was significantly elevated from baseline after CERA. Since cFGF23 levels were not affected by CERA + SFO, cFGF23 levels after CERA + SFO were significantly lower than those after CERA alone. The ratio of iFGF23 to cFGF23 (i/cFGF23 ratio) was significantly higher after CERA + SFO than that after CERA alone. In addition, high-sensitivity C-reactive protein (hsCRP) levels were significantly higher after CERA + SFO than after CERA alone.. Administration of SFO suppressed haematopoietic responses induced by CERA. Elevation of i/cFGF23 ratio and hsCRP could account for the inhibitory effects of SFO on haematopoiesis.. This study was registered with the University Hospital Medical Information Network (ID UMIN000016552 ).

Topics: Aged; Anemia; Biomarkers; Erythropoiesis; Erythropoietin; Female; Ferric Oxide, Saccharated; Fibroblast Growth Factor-23; Humans; Iron; Male; Peptide Hormones; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Dialysis patients with erythropoietin hypo-responsiveness suffered from refractory anemia. Roxadustat reversibly binds and inhibits hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD), resulting in increased endogenous EPO which stimulates erythropoiesis, theoretically has an advantage over exogenous EPO in anti-anemia therapy. From September 2019 to October 2020, 32 dialysis patients with hypo-responsiveness to erythropoietin were evaluated. During the 24-week follow-up period, all patients were taken off erythropoietin and switched to roxadustat. Dosage adjustments were administrated according to the fluctuation of hemoglobin level during the treatment. Parameters about anemia, iron metabolism and biochemical indexes were collected, and adverse events were recorded. A total of 31 patients completed the clinical observation, with varying degrees of malnutrition-inflammation. Post treatment, the levels of transferrin and total iron-binding capacity were increased, while that of transferrin saturation and cholesterol decreased. 15 cases (accounting for 48.39%, designated as fulfilled group) met the target level of hemoglobin, while 16 cases (51.61%, non-fulfilled group) did not. The baseline conditions of the above two groups were compared. The levels of hypersensitive C-reactive protein, interleukin-6 and serum ferritin in the non-fulfilled group were higher than those in the fulfilled group, and the levels of residual renal function, serum albumin, iron, transferrin and total iron-binding capacity were lower than those in the fulfilled group. Linear regression analysis showed that increase of HsCRP had a negative effect on the improvement of Hb. One case of adverse reaction grade 3 and four cases of grade 2 occurred throughout the study, yet all were relieved after therapy. Significant anti-anemia effects could be achieved in most patients with erythropoietin hypo-responsiveness after treatment with roxadustat, accompanied by relatively mild and rare adverse reactions. The malnutrition-inflammation states of patients may interfere with the anti-anemia effect of roxadustat, and iron utilization is more important than iron storage in anemia improvement.

Topics: Adult; Aged; Dialysis; Erythropoietin; Female; Glycine; Humans; Isoquinolines; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic

Recombinant human erythropoietin (rHuEPO) is effective in managing chronic kidney disease and chemotherapy-induced anemia. However, hyporesponsiveness to rHuEPO treatment was reported in about 10% of the patients. A decreased response in rats receiving a single or multiple doses of rHuEPO was also observed. In this study, we aimed to develop a quantitative systems pharmacology (QSP) model to examine hyporesponsiveness to rHuEPO in rats. Pharmacokinetic (PK) and pharmacodynamic (PD) data after a single intravenous dose of rHuEPO (100 IU/kg) was obtained from a previous study (Yan et al. in Pharm Res, 30:1026-1036, 2013) including rHuEPO plasma concentrations, erythroid precursors counts in femur bone marrow and spleen, reticulocytes (RETs), red blood cells (RBCs), and hemoglobin (HGB) in circulation. Parameter values were obtained from literature or calibrated with experimental data. Global sensitivity analysis and model-based simulations were performed to assess parameter sensitivity and hyporesponsiveness. The final QSP model adequately characterizes time courses of rHuEPO PK and nine PD endpoints in both control and treatment groups simultaneously. The model indicates that negative feedback regulation, neocytolysis, and depletion of erythroid precursors are major factors leading to hyporesponsiveness to rHuEPO treatment in rats.

Topics: Anemia; Animals; Bone Marrow; Erythrocytes; Erythropoietin; Evaluation Studies as Topic; Hemoglobins; Humans; Male; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic; Reticulocytes; Spleen

Anemia is a significant complication of chronic kidney disease (CKD), caused by erythropoietin deficiency and reduced iron availability. Erythropoiesis-stimulating agents have been used with iron supplementation to treat anemia; however, they are associated with some problems. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) is a promising new class of oral therapy for the treatment of anemia associated with CKD. HIF-PHI inhibits HIF-prolyl hydroxylase enzymes and results in the HIF-α accumulation, which leads to increased expression of HIF-responsive genes, including erythropoietin and vascular endothelial growth factor (VEGF). HIF stimulates endogenous erythropoietin production and also reduces circulating hepcidin concentrations, resulting in improved anemia. Many clinical trials demonstrate that HIF-PHI improves anemia in patients with CKD and on dialysis. In addition to treating anemia, HIF-PHI may have multiple potential effects. Several animal experiments show that HIF-PHI protects against ischemic kidney damage that progresses to CKD and also improves metabolic disorders and ameliorates cardiovascular complications. In contrast, malignant tumor and retinopathy should be carefully evaluated due to theoretical concerns that HIF stabilization may result in increased VEGF protein expression. Some adverse events such as shunt occlusion reported in large clinical trials also need attention and warrant further investigations.

Topics: Anemia; Animals; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic; Vascular Endothelial Growth Factor A

Objective: Roxadustat is a new medication for the treatment of renal anemia. EPO (erythropoietin)-the current treatment standard-has been reported to enhance platelet activation and production. However, to date, the effect of roxadustat on platelets is unclear. To address this deficiency, herein, we have evaluated the effect of roxadustat on platelet production and function.\ \ Approach and Results: We performed several mouse platelet functional assays in the presence/absence of in vitro and in vivo roxadustat treatment. Both healthy and 5/6 nephrectomized mice were utilized. The effect of roxadustat on platelet function of healthy volunteers and chronic kidney disease patients was also evaluated. For platelet production, megakaryocyte maturation and proplatelet formation were assayed in vitro. Peripheral platelet and bone marrow megakaryocyte counts were also determined. We found that roxadustat could not stimulate washed platelets directly, and platelet aggregation, spreading, clot retraction, and P-selectin/JON/A exposure were similar with or without in vitro or in vivo roxadustat treatment among both healthy and 5/6 nephrectomized mice. In vivo mouse thrombosis models were additionally performed, and no differences were detected between the vehicle and roxadustat treatment groups. EPO, which was considered a positive control in the present study, promoted platelet function and production as reported previously. Megakaryocyte maturation and proplatelet formation were also not significantly different between control mice and those treated with roxadustat. After receiving roxadustat for 14 days, no difference in the peripheral platelet count was observed in the mice.\ \ Conclusions: Administration of roxadustat has no significant impact on platelet production and function.

Topics: Animals; Blood Coagulation; Blood Platelets; Case-Control Studies; Disease Models, Animal; Erythropoietin; Glycine; Hematinics; Humans; Isoquinolines; Male; Mice, Inbred C57BL; Platelet Activation; Renal Insufficiency, Chronic; Thrombopoiesis; Thrombosis

Anemia is a common complication in patients with chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) are the standard therapy for anemia in CKD. It has been expected that hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibition may have the potential to provide therapeutic benefits over pre-existing ESAs for anemia in CKD. Enarodustat (JTZ-951) is an oral HIF-PH inhibitor. In preclinical studies, enarodustat has been found to increase HIF-alpha proteins, erythropoietin production and erythropoiesis. Enarodustat also shows efficient iron utilization in iron-related parameters during erythropoiesis. Clinical trials have shown that enarodustat improved anemia both in non-dialysis-dependent CKD patients and dialysis patients. The safety results in clinical trials demonstrate that enarodustat is generally well tolerated. On the basis of these results, enarodustat was approved in September 2020 in Japan for the treatment of anemia associated with CKD. This manuscript will review enarodustat, its pharmacological characteristics in preclinical studies, and its efficacy and safety in clinical trials with anemic patients in CKD.

Topics: Anemia; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; N-substituted Glycines; Pyridines; Renal Insufficiency, Chronic; Triazoles

Iron deficiency is a common etiology of anemia that causes suboptimal response to erythropoietin therapy in hemodialysis (HD) patients. This study investigated the association between vitamin D receptor (VDR) genetic variant (FokI) rs2228570 with iron indices (serum iron, transferrin, transferrin saturation, and ferritin). Sixty adequately hemodialyzed patients subdivided into two groups; 31 patients with transferrin saturation (TSAT) < 20% and 29 with TSAT > 20% who received I.V sodium ferric gluconate, calcium, and vitamin D. Sixty normal healthy were selected as the control group.. VDR genetic variant (SNP rs2228570) was genotyped in all subjects using PCR/RFLP. HD patients showed a higher frequency of rs2228570 FF genotype (38.3%) than controls (31.7%). The frequency of ff genotype and f allele in patients (8.4 and 35% respectively) were significantly lower than controls (25 and 46.7% respectively). Allele model (f vs. F): OR 0.721, 95% CI 0.521-0.998, P = 0.049. While (ff vs. FF): OR 0.452, 95% CI 0.223-0.917, P = 0.028. The distribution of Ff + ff genotypes in HD cases with TSAT > 20% was higher than in HD cases with TSAT < 20%, Dominant model (Ff +ff vs FF): OR 2.753, 95% CI 1.902-3.409, P = 0.048. f allele showed lower frequency in low TSAT group than high TSAT group (27.4 vs. 43.1%) with significant P value (P = 0.042) with allele model (f vs. F): OR 2.012, 95% CI 1.923-4.226, P = 0.042. Fok-1 ff, Ff + ff genotypes were significantly associated with TSAT > 20% with a protective effect against low TSAT in HD patients.

Topics: Adult; Anemia, Iron-Deficiency; Case-Control Studies; Erythropoietin; Female; Ferritins; Genetic Predisposition to Disease; Humans; Iron; Iron Deficiencies; Male; Middle Aged; Polymorphism, Genetic; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic; Transferrin

Previous studies suggested that endoplasmic reticulum (ER) stress induced-apoptosis promoted vascular calcification (VC). Interestingly, erythropoietin (EPO), an endogenous glycoprotein, exerts multiple tissue protective effects by inhibiting ER stress and apoptosis. We investigated the role and potential mechanism of EPO on VC in chronic kidney disease (CKD) rats and cultured vascular smooth muscle cells (VSMCs). The calcification model was established by subtotal nephrectomy in vivo or phosphate overload in vitro. The protein level of EPO receptor (EPOR) was increased in the calcified aortas of CKD rats. EPO prevented the reduction of VSMC phenotypic markers, and reversed the increased calcium content and calcium salt deposition in the aortas of CKD rats and cultured calcified VSMCs. The protein levels of activating transcription factor 4 (ATF4) and glucose-regulated protein 94 (GRP94) were upregulated in aortas and VSMCs under calcifying conditions, indicating ER stress activation. EPO treatment of CKD rats or calcified VSMCs downregulated the protein levels of ATF4 and GRP94. Furthermore, ER stress-mediated apoptosis, determined by the protein levels of CCAAT⁄enhancer-binding protein-homologous protein and cleaved caspase 12, was increased in tunicamycin or calcification media-treated VSMCs, but the increased effect was reversed in EPO-treated groups. The increased apoptotic cells in calcified VSMCs, as indicated by Hoechst staining and flow cytometry, were downregulated by the co-administration of EPO or 4-phenyl butyric acid. In conclusion, EPO might attenuate VC by inhibiting ER stress mediated apoptosis through EPOR signaling.

Topics: Activating Transcription Factor 4; Animals; Aorta; Cells, Cultured; Endoplasmic Reticulum Stress; Erythropoietin; Male; Membrane Glycoproteins; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Vascular Calcification

Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan.. Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data.. Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL. These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.

Topics: Adult; Anemia; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Development; Erythropoietin; Hematinics; Hemoglobins; Humans; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Prolyl hydroxylase (PHD) inhibitors are being developed as alternatives to recombinant human erythropoietin (rHuEPO) for the treatment of anemia in patients with chronic kidney disease (CKD). However, the effects of PHD inhibitors and rHuEPO on blood pressure and CKD in animal models susceptible to hypertension and nephropathy have not been studied. The present study compared the effects of dimethyloxaloylglycine (DMOG), a PHD inhibitor, and rHuEPO on the development of hypertension and renal injury in Dahl salt-sensitive rats fed an 8% salt diet for 3 weeks. DMOG and rHuEPO were equally effective at raising hemoglobin levels. Systolic blood pressure rose to a greater extent in rHuEPO-treated rats (267 ± 10 vs. 226 ± 4 mm Hg) than in rats given DMOG (189 ± 8 mm Hg). Urinary protein excretion increased to 568 ± 54 versus 353 ± 25 mg/day in rats treated with rHuEPO and vehicle; however, it only rose to 207 ± 21 mg/day in rats receiving DMOG. DMOG significantly attenuated the degree of glomerulosclerosis and renal interstitial fibrosis as compared with that in vehicle and rHuEPO-treated rats. This was associated with lower renal levels of monocyte chemoattractant protein-1 and interleukin-1

Topics: Amino Acids, Dicarboxylic; Anemia; Animals; Blood Pressure; Dose-Response Relationship, Drug; Erythropoietin; Fibrosis; Hemoglobins; Hypertension; Kidney; Male; Oxidative Stress; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Rats; Rats, Inbred Dahl; Recombinant Proteins; Renal Insufficiency, Chronic; Sodium Chloride, Dietary; Vascular Endothelial Growth Factor A

Scientific data regarding intravenous iron supplementation in peritoneal dialysis (PD) patients are scarce. In attempting to administer the minimum monthly IV iron dose that could improve erythropoiesis, we wanted to assess the safety and efficacy of monthly maintenance intravenous administration of 100 mg iron sucrose in PD patients.. In a 9-month prospective study, all clinically stable PD patients received intravenously 200 mg of iron sucrose as a loading dose, followed by monthly doses of 100 mg for five consecutive months. Levels of hemoglobin (Hb), ferritin, transferrin saturation (TSAT), reticulocyte hemoglobin content (CHr) and C-reactive protein (CRP) were measured before each administration and 3 months after the last iron infusion. Also, doses of concurrent erythropoietin administration were recorded.. Eighteen patients were eligible for the study. Mean levels of Hb and ferritin increased significantly (from 10.0 to 10.9 mg/dL, p = 0.01 and from 143 to 260 ng/mL, p = 0.005), as well as the increase in TSAT levels approached borderline significance (from 26.2 to 33.1%, p = 0.07). During the 6 months of iron administration, the erythropoietin dose was reduced in five patients and discontinued in one. During the 3 months following the last iron infusion, three of them again raised the erythropoietin dose to previous levels. None of the patients experienced any side effects related to IV iron administration.. A monthly maintenance intravenous dose of 100 mg iron sucrose may be a practical, effective, and safe in the short term, treatment of anemia in PD patients resulting in improved hemoglobin levels, iron indices, and erythropoietin response.

Topics: Administration, Intravenous; Aged; Aged, 80 and over; Anemia; C-Reactive Protein; Erythropoiesis; Erythropoietin; Female; Ferric Oxide, Saccharated; Ferritins; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Peritoneal Dialysis; Prospective Studies; Renal Insufficiency, Chronic; Reticulocytes; Transferrin

Renal anemia in chronic kidney disease is treated with recombinant human erythropoietin (rhEPO). However, some patients with anemia do not respond well to rhEPO, emphasizing the need for a more biocompatible EPO. Differentiation protocols for hepatic lineages have been modified to enable production from human induced pluripotent stem cell (hiPSC)-derived EPO-producing cells (EPO cells). However, markers for hiPSC-EPO cells are lacking, making it difficult to purify hiPSC-EPO cells and therefore to optimize EPO production and cell counts for transplantation. To address these issues, we investigated whether CD140b and CD73 could be used as markers for hiPSC-EPO cells. We measured the expression of EPO, CD140b, and CD73 in hiPSC-EPO cells and the EPO concentration in the cell supernatant by immunohistochemistry and enzyme-linked immunosorbent assays on culture day 13, revealing that expression levels of CD140b and CD73 are correlated with the level of EPO. In addition, rates of CD140b

Topics: 5'-Nucleotidase; Anemia; Biomarkers; Cell Differentiation; Erythroid Precursor Cells; Erythropoietin; GPI-Linked Proteins; Humans; Induced Pluripotent Stem Cells; Receptor, Platelet-Derived Growth Factor beta; Renal Insufficiency, Chronic

Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels (

Topics: Adult; Aged; Anemia; Biomarkers; Brazil; Cells, Cultured; Clinical Decision-Making; Databases, Factual; Erythropoiesis; Erythropoietin; fas Receptor; Female; Hematinics; Hematopoietic Stem Cells; Hemoglobins; Humans; Male; Middle Aged; Multipotent Stem Cells; North Carolina; Patient Selection; Predictive Value of Tests; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies

Topics: Animals; Cyclosporine; Cytokines; Erythropoietin; Fibrosis; Inflammation; Kidney; Male; PPAR gamma; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Toll-Like Receptor 4; Transforming Growth Factor beta1

Iron and erythropoietin deficiencies are determinants of anemia in chronic kidney disease. In hemodialysis (HD) patients, intravenous (IV) iron is associated with a greater hemoglobin (Hb) production and better erythropoietin response but may be associated to hypersensitivity reaction. After the 2013 European Medicines Agency report regarding early detection/management of iron allergic reactions, IV iron administration dramatically reduced in Italian Hemodialysis-Limited-Assistance-Centre (HD-CAL) where a physician is present only once a week. Objective of the study was providing an effective and secure IV iron administration protocol for HD-CAL patients. IV ferric carboxymaltose (FCM) administration was more effective and better tolerated than sodium ferric gluconate for iron deficiency correction and resolution of anemia in 24 patients undergoing HD in our HD-CAL. Six months of FCM IV treatment once a week increased ferritin and Hb compared to sodium ferric gluconate once a week leading to decreased erythropoietin consumption from 24 000 to 15 000 U/patient/week with an erythropoietin annual expense reduction. No blood transfusions, gastrointestinal intolerance or other adverse effects were reported. The FCM IV administration protocol for our HD-CAL patients was safe and no adverse events were reported, resulting in significantly increased ferritin, transferrin saturation, and Hb levels, reduction of erythropoietin requirements, and consequently reduction of erythropoietin expenses.

Topics: Administration, Intravenous; Ambulatory Care Facilities; Anemia, Iron-Deficiency; Clinical Protocols; Costs and Cost Analysis; Erythropoietin; Female; Ferric Compounds; Ferritins; Hematinics; Humans; Iron; Italy; Male; Maltose; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

To establish adherence to treatment with erythropoiesis stimulating agents (ESA) in patients with anemia associated to chronic kidney disease (CKD), and analyze its relationship to response to ESA.. Retrospective study of a cohort of 198 patients with CKD who started treatment with epoetin-ß or darbepoetin-a, followed for two years. Basal characteristics, effectiveness (% of hemoglobin (Hb) target attainment, percentage increase of Hb) and adherence (medication possession rate) were registered. A non-adherent patient was one whose mean adherence was <90%.. Average global adhesion was 89.6%, slightly higher in treatment with darbepoetin-a than with epoetin-ß; 8.6% of patients were non-adherents. Hb target was accomplished in 87% cases. Level of response to ESA treatment was independent of the degree of adherence to treatment.. Adherence to ESA treatment was good, without differences related to degree of response.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobin A; Humans; Male; Medication Adherence; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors

To evaluate the impact of a nurse prescriber-led protocol compared to a traditional physician-led nonprotocol-based approach had on maintaining targeted haemoglobin levels in patients on maintenance haemodialysis.. Anaemia is a common complication of chronic kidney disease and has a profound impact on the patients' well-being. Current practices place a greater emphasis on the decision-making role of nurses in renal anaemia management. The introduction of nurse prescribing in this area is a relatively new concept.. A retrospective cohort design, covering an eight-month period pre- and post introduction of a nurse prescriber-led anaemia protocol; study adheres to the STROBE Statement.. Using a nonprobability convenience sample, data extracted from the medical records and electronic patient records system (eMed) related to 74 patients at a single outpatient haemodialysis centre located within an acute general teaching hospital. The primary outcome was patients' haemoglobin level pre- and post introduction of the protocol. Secondary outcomes included erythropoietin-stimulating agent and iron dosage, and serum ferritin and transferrin saturation levels.. There were no statistically significant differences between pre- and post protocol serum haemoglobin level and erythropoietin-stimulating agent dosage. Under the management of the nurse prescriber, patients experienced a significant improvement in serum ferritin and transferrin saturation levels and required significantly less intravenous iron dosage.. This study, the first of its kind, found that patients receiving haemodialysis experience a significant improvement in iron indices while receiving a significantly lower amount of intravenous iron when managed by a nurse prescriber. Furthermore, the nurse prescribers' decision-making capacity is as effective as a physician-led nonprotocol-based approach in achieving haemoglobin target levels.. Nurse prescribers have a role in implementing a safe, standardised and sustained approach to anaemia management in outpatient haemodialysis settings without compromising patient care.

Topics: Adult; Anemia; Cohort Studies; Erythropoietin; Female; Humans; Male; Middle Aged; Practice Patterns, Nurses'; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies

Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.

Topics: Anemia; Animals; Antibodies, Monoclonal; Arthritis; Bone Marrow; Bone Morphogenetic Protein 6; Cation Transport Proteins; Cytokines; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Synergism; Erythropoietin; Hep G2 Cells; Humans; Iron; Mice; Muscle Proteins; Polysaccharides, Bacterial; Random Allocation; Recombinant Proteins; Renal Insufficiency, Chronic

Iron-deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor-23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) FG-4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 ("iFGF23"). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild-type mice were fed an adenine-containing diet to induce CKD, then injected with EPO or FG-4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG-4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein-6 (Bmp-6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF-PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.

Topics: Anemia; Animals; Bone Morphogenetic Protein 6; Cytokines; Disease Models, Animal; Erythropoietin; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hepcidins; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice, Inbred C57BL; Muscle Proteins; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Erythropoiesis; Erythropoietin; Glycine; Haplorhini; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Rats; Renal Insufficiency, Chronic

Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here.. Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions.. CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon's epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration.. Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters.

Topics: Animals; Colon; Erythropoietin; Ferric Compounds; Hyperphosphatemia; Intestinal Absorption; Iron; Male; Phosphates; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tissue Distribution

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Homeostasis; Humans; Male; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia, Refractory; Autoantibodies; Bone Marrow; Erythropoietin; Female; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Middle Aged; Renal Insufficiency, Chronic; Treatment Outcome

The application of erythropoietin (EPO) can bring about a rare but serious complication called anti-EPO antibody-mediated pure red cell aplasia (PRCA). Once the disease is diagnosed, EPO administration should be stopped immediately. However, after the removal of the anti-EPO antibody, treating anaemia in these patients with chronic renal disease with EPO therapy is difficult, as restarting EPO therapy risks the recurrence of anti-EPO antibody-mediated PRCA. A 26-year-old man with anaemia related to renal failure, who was administered recombinant human EPO subcutaneously, developed anti-EPO antibody-mediated PRCA. After removal of antibodies by treatment with corticosteroids and cyclosporine, therapy for anaemia of chronic renal disease with roxadustat achieved good results. Roxadustat is a new type of drug for the treatment of anaemia, and it can stimulate endogenous EPO within or near the physiologic range and increase haemoglobin levels.

Topics: Adult; Erythropoietin; Glycine; Humans; Isoquinolines; Male; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16-2.19) and age (sHR = 1.03, 1.02-1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-β. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.

Topics: Adult; Aged; Anemia; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Interleukin-1; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Aged; Anemia; Erythropoietin; Female; Ferritins; Genetic Markers; Glomerular Filtration Rate; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1beta; Male; Middle Aged; Renal Insufficiency, Chronic

Anemia is a common chronic kidney disease (CKD) complication contributing to increased morbidity and mortality. Collagen-based traditional Chinese nutraceuticals have long been used in antianemic therapies. This study aims to investigate the therapeutic effectiveness of porcine collagen hydrolysate (CH) and its underlying mechanism in the treatment of renal anemia by using adenine-induced CKD mice, RAW264.7 macrophages, and HepG2 hepatoma cells, with prolyl-hydroxyproline as a reference compound for collagen-derived hydroxyproline-containing di-/tripeptides. CH was found to alleviate renal filtering dysfunction, systemic and kidney inflammation, liver hepcidin overproduction and anemia and to increase erythropoietin production and hypoxia inducible factor (HIF)-2α stability in liver and kidney in CKD mice. Prolyl-hydroxyproline exerted direct anti-inflammatory effects on lipopolysaccharide-activated macrophages and elicited stimulating and inhibiting activities on erythropoietin expression and hepcidin overproduction, respectively, in HepG2 cells by HIF-2α activation. Overall, CH was effective in correcting renal anemia via anti-inflammatory renoprotection and HIF-2α-dependent erythropoietin and hepcidin regulation.

Topics: Anemia; Animals; Anti-Inflammatory Agents; Collagen; Erythropoietin; Female; Hepcidins; Humans; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Protein Hydrolysates; Renal Insufficiency, Chronic; Swine; Transcription Factors

Roxadustat (Rox), a hypoxia-inducible factor (HIF) stabilizer, is now available for the treatment of anemia in hemodialysis (HD) patients. To investigate hematopoietic effect and iron metabolism, this study involved 30 HD patients who were initially treated with darbepoetin (DA), a conventional erythropoietin-stimulating agent, and then switched to Rox. We measured erythrocyte, reticulocyte indices, and iron-related factors at every HD during the first two weeks after the treatment switch (Days 0-14) and again on Days 21 and 28. We measured erythropoietin (EPO) concentration every week and examined their changes from Day-0 values. The same variables were measured in 15 HD patients who continued DA at every HD for one week. Iron-related factors were also measured on Days 14 and 28. In the Rox group, hepcidin significantly decreased from Day 2. The reticulocyte hemoglobin content (CHr) significantly increased on Day 4, but decreased with a significant increase in reticulocyte count from Day 7. Log

Topics: Aged; Aged, 80 and over; Anemia; Cell Count; Darbepoetin alfa; Drug Substitution; Erythrocytes; Erythropoietin; Female; Ferritins; Gene Expression Regulation; Glycine; Hematinics; Hematopoiesis; Hemoglobins; Hepcidins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Isoquinolines; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Reticulocytes; Transferrin; Treatment Outcome

Anemia and iron deficiency are highly prevalent in chronic kidney disease (CKD) and in chronic heart failure. Both may epidemiologically predict future renal and/or cardiovascular events. However, anemia treatment with either erythropoietin or erythropoiesis-stimulating agents failed to induce a prognostic benefit in either CKD or chronic heart failure. Instead, in the subgroup of chronic dialysis patients, liberal intravenous iron supplementation was beneficial, and ongoing clinical trials are testing the prognostic implication of intravenous iron supplementation in chronic heart failure. Finally, HIF stabilizers are a new treatment option for anemia in chronic kidney disease, and safety studies are currently ongoing in CKD patients. Whether patients suffering from chronic heart failure might also benefit from this treatment is currently unknown.. THERAPIE MIT EISENPRäPARATEN:  Mit PIVOTAL erschien 2018 die erste kardiovaskuläre Endpunktstudie zur Eisensubstitution bei Dialysepatienten, die eine prognostische Überlegenheit einer Hochdosiseisentherapie gegenüber einer restriktiveren Eisenapplikation aufzeigte. Mit AFFIRM-AHF, IRONMAN, FAIR-HF2 und HEART-FID überprüfen aktuell gleich 4 Studien die Bedeutung einer intravenösen Eisenapplikation auf kardiovaskuläre Endpunkte bei Patienten mit Herzinsuffizienz. AUSBLICK:  HIF-Stabilisatoren erlauben eine orale Anämie-Behandlung bei chronischer Nierenerkrankung. Erste klinische Studien zeigten eine „Nichtunterlegenheit“ von HIF-Stabilisatoren gegenüber der Behandlung mittels rekombinanten Erythropoetins (EPO)/Erythropoese-stimulierenden Agenzien (ESA) in Bezug auf den Hämoglobinanstieg. Finale Ergebnisse großer Studien mit kardiovaskulären Endpunkten sind aktuell noch ausstehend. In diesen Studien muss das Sicherheitsprofil von HIF-Stabilisatoren überprüft werden, da HIF-Stabilisatoren die Transkription zahlreicher Gene auch jenseits der Hämatopoese verändern. In der klinischen Kardiologie spielen HIF-Stabilisatoren aktuell (noch) keine Rolle. Unter der Therapie mittels SGLT-II-Inhibitoren konnte ein Anstieg des Hämatokrits beobachtet werden, welcher sich nicht allein durch diuretische Effekte erklären lässt. Die genaue pharmakodynamische Wirkweise ist noch offen.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Renal Dialysis; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) can cause anaemia and neurological disorders. Recombinant human erythropoietin (rHuEPO) is used to manage anaemia in CKD. However, there is little evidence on the effects of rHuEPO on behaviour and cognitive function in CKD. This study aimed to evaluate the impact of rHuEPO in sensorimotor and cognitive functions in a CKD model.. Male Wistar rats were randomly assigned to 4 groups: control and CKD, with and without rHuEPO treatment (1050 IU per kg body weight, once weekly for 4 weeks). The Morris water maze, open field, and adhesive removal tests were performed simultaneously to kidney damage induction and treatment. Markers of anaemia and renal function were measured at the end of the study.. Treatment with rHuEPO reduced kidney damage and corrected anaemia in rats with CKD. We observed reduced sensorimotor dysfunction in animals with CKD and treated with rHuEPO. These rats also completed the water maze test in a shorter time than the control groups.. rHuEPO reduces kidney damage, corrects anemia, and reduces sensorimotor and cognitive dysfunction in animals with CKD.

Topics: Anemia; Animals; Cognitive Dysfunction; Erythropoietin; Humans; Iron; Male; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic

Cognitive dysfunction potentially affecting up to 60% of CKD patients. GSK-3β plays a key role in the pathogenesis of AD and Cognitive dysfunction, contributing to Aβ production and Aβ-mediated neuronal death by phosphorylating tau inducing hyperphosphorylation in paired helical filaments. However, studies have shown that plasma p-Tau181 is more specific for AD and cognitive dysfunction. Anemia is a vital risk factor for cognitive dysfunction in CKD patients. EPO is usually to treat anemia in CKD and also improved in cognitive function. The aim of the study is to correlate between the impacts of rHuEPO therapy on platelet GSK3β expression, plasma Aβ. The subjects, 30 CKD without cognitive dysfunction and 30 CKD with cognitive dysfunction patients. To correlate abnormal proteins with neuropsychological tests scoring in CKD with cognitive dysfunction subjects after the six months rHuEPO therapy.. The p < 0.05 is considered as statistically significant. Pearson and Spearman correlation coefficient was used to determine the potential relationship between abnormal proteins with neuropsychological tests scoring in respective experimental groups.. The use of abnormal protein levels, preferably in association with neuropsychological assessment total scores, appears to be a potential tool that can improve the CKD with cognitive dysfunction diagnosis. In post rHuEPO treatment, the altered protein abnormalities and neuropsychological assessment scores were retrieved significantly compared to pre treatment determined the clinical usefulness of rHuEpo as supplemental therapeutic agent in cognitive dysfunction in CKD.

Topics: Adult; Amyloid beta-Peptides; Anemia; Biomarkers; Cognitive Dysfunction; Erythropoietin; Female; Glycogen Synthase Kinase 3 beta; Humans; Male; Middle Aged; Neuropsychological Tests; Recombinant Proteins; Renal Insufficiency, Chronic; tau Proteins

Impaired orthostatic blood pressure (BP) stabilization is prevalent in patients with chronic kidney disease (CKD) and is associated with adverse outcomes. We aimed to test the hypothesis that reduced hemoglobin is an important contributor to orthostatic intolerance in CKD in the present study. This study included 262 patients with non-dialysis-dependent CKD. Seated and standing BP was measured, and orthostatic BP reduction was calculated for both systolic BP (∆ SBP) and diastolic BP (∆ DBP). The association between orthostatic BP reduction and hemoglobin was determined by multiple linear regression models. We also performed mediation analysis to test to what extent the effect of renal dysfunction on impaired orthostatic BP stabilization can be explained by reduced hemoglobin. The mean age of the patients was 57.7 (±14.5) years, and 61.5% were male. Both ∆ SBP and ∆ DBP correlated negatively with estimated glomerular filtration rate (eGFR). With adjustment for age and sex, hemoglobin level was negatively associated with ∆ SBP (β = -1.4, SE = 0.4, P < .001) and ∆ DBP (β = -0.6, SE = 0.2, P = .009). The associations remained significant with further adjustment for additional covariates. When eGFR was introduced as a covariate, it did not eliminate the significance (both P < .05). The associations remained essentially unchanged in a sensitivity analysis excluding those with concurrent erythropoietin use. Mediation analysis demonstrated that reduced hemoglobin accounted for 35.4% (P = .004) of the effect of eGFR on ∆ SBP and 47.7% (P = .032) on ∆ DBP. Our study suggests that reduced hemoglobin is a potentially important contributor to the development of orthostatic hypotension in CKD.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Determination; Case-Control Studies; China; Cross-Sectional Studies; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Hypotension, Orthostatic; Male; Middle Aged; Posture; Prevalence; Pulse Wave Analysis; Renal Insufficiency, Chronic

Evidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice.. During the years 2009-2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out.. In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0-1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2-2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1-2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2-0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3-0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness.. The study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients' quality of life.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Forecasting; Hematinics; Humans; Italy; Male; Middle Aged; Neoplasms; Population Surveillance; Renal Insufficiency, Chronic; Retrospective Studies

Fibroblast Growth Factor 23 (FGF23) is a phosphaturic factor causing increased renal phosphate excretion as well as suppression of 1,25 (OH)

Topics: Amino Acids; Animals; Bone Density; Calcification, Physiologic; Calcitriol; Calcium; Erythropoietin; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Kidney; Mice; Mice, Inbred C57BL; Mice, Transgenic; Minerals; Osteocalcin; Phosphates; Renal Insufficiency, Chronic

Topics: Anemia; Erythropoietin; Humans; Polyethylene Glycols; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Republic of North Macedonia

Anaemia among haemodialysis patients is treated with iron and erythropoietin-stimulating agents (ESAs). ESAs reduce requirements for blood transfusions but are also expensive and overzealous use may be associated with adverse outcomes. Recent international trends have been characterised by reduced ESA doses and a greater reliance on intravenous (IV) iron. We determined trends in prescribing patterns of ESAs and IV iron for the treatment of anaemia in two representative Irish dialysis centres and correlated with current guidelines and international trends.. Patient data was accessed from the Kidney Disease Clinical Patient Management System (KDCPMS) for the period 2012 to 2014. We generated reports on ESA and iron doses, lab data (haemoglobin (Hb), transferrin saturation (TSAT) and ferritin) and patient population characteristics. We mapped the trends in ESA, iron dosing and lab parameters achieved. A linear mixed model determined the significance of these trends over time.. ESA dosing became lower in the second, third and fourth quarters of 2014. Dosing of iron increased throughout but a large increase was seen in the third and fourth quarters of 2014. Ferritin levels decreased and TSAT and haemoglobin levels increased. Changes in iron dosing were significant with p value of < 0.05.. Our findings are consistent with recent global trends toward increasing iron use. Such trends may have economic implications given the high cost of ESAs and the relative affordability of iron. In addition, the potential harm of excessive iron dosing may need to be considered.

Topics: Aged; Anemia; Cohort Studies; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Iron; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Trace Elements; Transferrin

Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models.. We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose.. Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models.. EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

Topics: Animals; beta-Thalassemia; Cohort Studies; Erythropoietin; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Kidney Transplantation; Male; Mice; Mice, Transgenic; Middle Aged; Prognosis; Renal Insufficiency, Chronic

Relatively few haemodialysis (HD) patients remain independent of recombinant human erythropoietin ('rHU-EPO free patients'). We investigated the role of EPO and hepcidin, two key hormones involved in anaemia.. We report a monocentric case-control series. Iron status, EPO and hepcidin levels were analysed in 15 Adult HD (Age > 18 years) with a stable haemoglobin (Hb) level that have not received rHU-EPO for at least 6 months (=rHU-EPO free patients); and in 60 controls with a stable rHU-EPO dose and Hb level.. The rHU-EPO free patients had a higher Hb level compared to controls (12.1 ± 0.99 g/dL vs 11.1 ± 0.73, P = 0.0014), and a lower ferritin level (183 ± 102 vs 312 ± 166 ng/mL, P = 0.001). Hepcidin levels were lower in the rHU-EPO free patients (12.53 ± 10.46 ng/mL) compared to the controls (37.95 ± 34.33 ng/mL), P = 0.0033. Hepcidin levels correlated significantly with ferritin levels; but neither with transferrin saturation, C-reactive protein nor EPO levels. Unsupervised analysis revealed that rHU-EPO free patients had a specific clinical/biological profile (presence of renal cyst, longer dialysis vintage, lower ferritin, and EPO and hepcidin levels compared to the control group). Finally, we showed that a lower ferritin level might be a surrogate marker of a lower hepcidin status in this population.. Recombinant human erythropoietin free patients seem to restore the EPO-hepcidin axis that is critical for erythropoiesis. A specific combination of clinical and biological parameters may help to detect future rHU-EPO free patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Ferritins; Hepcidins; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Although the primary cause of anemia in chronic kidney disease (CKD) is lack of sufficient erythropoietin (EPO), other factors may be involved, including the deregulation of iron metabolism. To clarify the mechanism of deranged erythropoiesis in CKD, we evaluated bone marrow (BM) cells in adenine-induced CKD mice. They showed even higher EPO expression in the kidney. Hepatic hepcidin mRNA and plasma hepcidin and ferritin levels were increased. Flow cytometry revealed a decrease in the number of cells expressing transferrin receptor (TfR), or late erythroid progenitors in BM; these cells correspond to proerythroblasts, and basophilic and polychromatic erythroblasts. In CKD mice, levels of erythroferrone mRNA in BM and splenic cells were significantly decreased, and MafB protein levels in BM cells were significantly increased. These results suggest that, in BM, the decrease in TfR, which may be associated with increased MafB levels, and the decrease in erythroferrone increase hepatic hepcidin expression, which may perturb iron recycling and erythropoiesis.

Topics: Adenine; Animals; Bone Marrow; Cytokines; Erythropoiesis; Erythropoietin; Hepcidins; Iron; Kidney; MafB Transcription Factor; Mice; Muscle Proteins; Receptors, Transferrin; Renal Insufficiency, Chronic

Vascular calcification is common in chronic kidney disease (CKD) patients, while erythropoietin (EPO) is widely used in the treatment of renal anemia in CKD patients, whether there is a link between the two is still not clear.. The primary rat vascular smooth muscle cells (VSMCs) and CKD rats were treated with EPO and the calcium deposition was observed by alizarin red staining, von Kossa staining and calcium quantification. Activation of JAK2/STAT3/BMP-2 axis and NF-κB signaling pathways was investigated by Western blotting.. EPO-induced calcium deposition in VSMCs and significantly potentiated calcification in CKD rats. Furthermore, EPO activated JAK2/STAT3/BMP-2 axis, NF-κB pathway and the pro-calcification effect of EPO was partially blocked by the STAT3 inhibitor (Cryptotanshinone) or NF-κB inhibitor (BAY 11-7082), respectively, in vitro.. EPO could promote VSMCs calcification in vitro and in vivo and this effect may be achieved through the JAK2/STAT3/BMP-2 axis and NF-κB pathway.

Topics: Alkaline Phosphatase; Anemia; Animals; Bone Morphogenetic Protein 2; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Erythropoietin; Gene Expression; Janus Kinase 2; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Nitriles; Phenanthrenes; Phosphorylation; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Signal Transduction; STAT3 Transcription Factor; Sulfones; Up-Regulation; Vascular Calcification

Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney and liver limit the understanding of Epo dysregulation in polycythaemia and anaemia. To overcome this limitation, we have generated a novel transgenic mouse model expressing Cre recombinase specifically in the active fraction of renal Epo-producing (REP) cells. Crossing with reporter mice confirmed the inducible and highly specific tagging of REP cells, located in the corticomedullary border region where there is a steep drop in oxygen bioavailability. A novel method was developed to selectively grow primary REP cells in culture and to generate immortalized clonal cell lines, called fibroblastoid atypical interstitial kidney (FAIK) cells. FAIK cells show very early hypoxia-inducible factor (HIF)-2α induction, which precedes Epo transcription. Epo induction in FAIK cells reverses rapidly despite ongoing hypoxia, suggesting a cell autonomous feedback mechanism. In contrast, HIF stabilizing drugs resulted in chronic Epo induction in FAIK cells. RNA sequencing of three FAIK cell lines derived from independent kidneys revealed a high degree of overlap and suggests that REP cells represent a unique cell type with properties of pericytes, fibroblasts, and neurons, known as telocytes. These novel cell lines may be helpful to investigate myofibroblast differentiation in chronic kidney disease and to elucidate the molecular mechanisms of HIF stabilizing drugs currently in phase III studies to treat anemia in end-stage kidney disease.

Topics: Anemia; Animals; Cell Hypoxia; Cell Line; Erythropoietin; Feedback, Physiological; Kidney; Mice; Mice, Transgenic; Primary Cell Culture; Renal Insufficiency, Chronic; Telocytes; Transcription Factors

Topics: Anemia; Cross-Sectional Studies; Drug Costs; Epoetin Alfa; Erythropoietin; Female; Health Personnel; Hematinics; Humans; Male; Panama; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors

Patient's perception analysis appears recently in numerous studies. Conjoint analysis has been used extensively by market researchers for studying how people value the characteristics of products and services. This technique was used in a clinical study to describe perceptions and preferences of anaemic patients suffering from chronic kidney disease not on dialysis (CKDnd), regarding erythropoietin stimulating agents (ESA).. PERCEPOLIS was a French multicenter prospective non-interventional study designed to describe the relative importance of ESA attributes according to CKDnD patients. Patients fulfilled questionnaires using an electronic device (digital tablet) at baseline and after 6 months under continuous erythropoietin receptor activator (CERA) treatment. Choice-based conjoint (CBC) questionnaires were developed with multiple components: 7 ESA attributes (2 or 3 levels per attribute), 2 partial profiles per task (2 out of the 7 attributes), and 7 tasks per questionnaire. Analyses were performed according to previous ESA treatment or not.. From 789 analyzed patients, 433 non ESA-naive patients were more than 80% to declare treatment efficacy as the most important expectative in ESA choice process (direct question) but CBC analyses revealed that frequency of injections was more crucial (relative mean weight: ∼30% versus ∼20% for efficacy). Pain at injection site and haemoglobin not exceeding the recommended target were confirmed as important criteria for patients (relative mean weights: ∼15%). No new or unexplained safety signals were noted.. Using CBC design for the first time in a non-interventional ESA study with an electronic Patient Reported Outcome (ePRO) in an elderly population, these data showed that monthly injections and treatment efficacy were key patients' expectations relative to ESAs. CERA efficacy to maintain stable haemoglobin within the recommended range was confirmed in real-life conditions.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Patient Preference; Patient-Centered Care; Prospective Studies; Renal Insufficiency, Chronic

Real-world data on the comparative effectiveness and safety of switching among different epoetins (including originators and biosimilars) are limited. In light of current debate about interchangeability, prescribers, some patient groups and decision makers are calling for additional post-marketing evidence on the clinical effects of switching between originator and biosimilar epoetins in chronic kidney disease (CKD) patients.. The objective of this study was to evaluate the effectiveness and safety of switching versus non-switching and of switching from originator/biosimilar epoetin alpha (ESA α) to any other epoetin in CKD patients.. An observational, record-linkage, multi-database, retrospective cohort study was carried out in four Italian geographical areas. All subjects with at least one ESA α dispensing between 1 January 2009 and 31 December 2015 were retrieved. Switching was defined as any transition between originator/biosimilar ESA α to any other epoetin in a series of two consecutive prescriptions up to 2 years. Switchers were matched 1:1 with non-switchers by baseline propensity score and by duration of ESA α treatment. Switchers and non-switchers were followed up from switching date to a maximum of 1 year. Lack of effectiveness and safety of switching versus non-switching were evaluated through Cox regression models (hazard ratio [HR], 95% confidence interval [CI]). A direct comparison between the two switcher categories (switchers from originator/biosimilar ESA α to any other epoetin) was also performed.. Overall, 14,400 incident users of ESA α for anaemia due to CKD (61.4% originator, 38.6% biosimilar) were available for analysis. During the follow-up, we found no differences on effectiveness (HR 1.02, 95% CI 0.79-1.31 originators; HR 1.16, 95% CI 0.75-1.79 biosimilars) and safety outcomes (HR 1.08, 95% CI 0.77-1.50 originators; HR 1.20, 95% CI 0.66-2.21 biosimilars) between switchers and non-switchers of ESA α. Cumulative probabilities of recording an adverse event, either in terms of lack of effectiveness or safety issue, were the same for two switching categories CONCLUSIONS: In this large-scale Italian observational multi-database study, switching versus non-switching as well as switching from biosimilar/originator ESA α to any other epoetin in CKD patients is not associated with any effectiveness and safety outcomes.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Cohort Studies; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Italy; Male; Medical Record Linkage; Middle Aged; Product Surveillance, Postmarketing; Propensity Score; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

The erythroid growth factor erythropoietin (Epo) is produced by renal interstitial fibroblasts, called REP (renal Epo-producing) cells, in a hypoxia-inducible manner. In chronic kidney disease (CKD), REP cells lose their Epo-production ability, leading to renal anaemia. Concurrently, REP cells are suggested to be transformed into myofibroblasts, which are the major player of renal fibrosis. Although establishment of cultured cell lines derived from REP cells has been a long-term challenge, we here successfully established a REP-cell-derived immortalized and cultivable cell line (Replic cells) by using a genetically modified mouse line. Replic cells exhibited myofibroblastic phenotypes and lost their Epo-production ability, reflecting the situation in renal fibrosis. Additionally, we found that cell-autonomous TGFβ signalling contributes to maintenance of the myofibroblastic features of Replic cells. Furthermore, the promoters of genes for Epo and HIF2α, a major activator of Epo gene expression, were highly methylated in Replic cells. Thus, these results strongly support our contention that REP cells are the origin of myofibroblasts in fibrotic kidneys and demonstrate that cell-autonomous TGFβ signalling and epigenetic silencing are involved in renal fibrosis and renal anaemia, respectively, in CKD. The Replic cell line is a useful tool to further investigate the molecular mechanisms underlying renal fibrosis.

Topics: Anemia; Animals; Cell Line; Disease Models, Animal; Embryo, Mammalian; Epigenesis, Genetic; Erythropoietin; Fibroblasts; Fibrosis; Humans; Kidney; Male; Mice; Mice, Transgenic; Myofibroblasts; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta1

Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF-2α protein decreased, whereas focal adhesion kinase protein (FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV. Proteasome inhibition or FAK inactivation in cells plated on collagen I restored erythropoietin and HIF-2α expression. FAK inhibition also decreased the collagen I-dependent proteasome activation. In a model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice, increased collagen I protein content and an almost complete disappearance of erythropoietin mRNA expression were observed in the ureteral ligated kidney with respect to the contralateral control. Interestingly, erythropoietin synthesis was recovered in obstructed mice treated with proteasome inhibitor. These data suggest that reduced kidney erythropoietin synthesis could be caused by the accumulation of abnormal extracellular matrix proteins.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Collagen Type I; Down-Regulation; Erythropoietin; Extracellular Matrix; Fibroblasts; Fibrosis; Focal Adhesion Protein-Tyrosine Kinases; Humans; Kidney; Mice, Inbred C57BL; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Renal Insufficiency, Chronic; RNA, Messenger; Ureteral Obstruction

Chronic kidney disease (CKD) is accompanied by a variety of complications, typically renal anemia and kidney fibrosis. Accordingly, it is desirable to develop the novel therapeutics that can treat these CKD conditions. Since nitric oxide (NO) has multiple functions including hypoxia inducible factor stabilizing, anti-inflammatory, anti-oxidative, and anti-apoptoic activities, the use of NO for the CKD therapy has attracted considerable interest. Here, we evaluate the therapeutic impacts of S-nitrosated human serum albumin (SNO-HSA), a long-lasting NO donor, on 2 animal models of CKD. SNO-HSA increased the expression of erythropoietin (EPO), VEGF, and eNOS by stabilizing hypoxia inducible factor-1α in HepG2 and HK-2 cells. SNO-HSA increased hematopoiesis in both healthy and renal anemia rats, suggesting the promotion of EPO production. In unilateral ureteral obstruction-treated mice, SNO-HSA ameliorated kidney fibrosis by suppressing the accumulation of renal extracellular matrix. SNO-HSA also inhibited unilateral ureteral obstruction-induced α-smooth muscle actin increase and E-cadherin decrease, suggesting that SNO-HSA might suppress the accumulation of myofibroblasts, an important factor of fibrosis. SNO-HSA also inhibited the elevations of fibrosis factors, such as transforming growth factor-β, interleukin-6, and oxidative stress, while it increased EPO production, an anti-fibrosis factor. In conclusion, SNO-HSA has the potential to function as a dual therapeutics for renal anemia and kidney fibrosis.

Topics: Anemia; Animals; Cell Line, Tumor; Erythropoietin; Fibrosis; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Mice; Mice, Inbred ICR; Models, Theoretical; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Nitroso Compounds; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Serum Albumin, Human; Vascular Endothelial Growth Factor A

Anaemia is one of the hallmarks of advanced chronic kidney disease (CKD); it correlates with a lower quality of life and increased cardiovascular risk. Currently its management is based on iron and erythropoiesis-stimulating agents (ESAs) therapy. Given safety issues on ESA therapy and excessive iron use, anaemia management is still suboptimal. Areas covered: The inhibitors of the prolyl-hydroxylases domain (PHD) are oral drugs which activate the hypoxia-inducible factors (HIF) and stimulate the production of endogenous erythropoietin. Roxadustat (FG-4592) is a second-generation PHD inhibitor; it is undergoing now phase-III clinical development. Expert opinion: Phase-II clinical trials have shown that roxadustat is effective and save in the short term in either non-dialysis or dialysis CKD patients. Roxadustat is a chemical drug and thus has the potential of being cheaper than traditional ESAs. Given that the peaks of endogenous EPO are much lower than those observed with traditional ESA, it is possible to speculate the roxadustat (and more in general PHD inhibitors) will be safer than ESA on cardiovascular safety end-points. Considering that HIFs are involved in different pathways, with possible promotion of relevant side effects, their safety must be proven in long-term studies.

Topics: Anemia; Animals; Cardiovascular Diseases; Erythropoietin; Glycine; Hematinics; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

Epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) is currently widely used for the treatment of anemia associated with chronic kidney disease (CKD). Therapeutic control of anemia is assessed by monitoring haemoglobin (Hb) levels. However, certain qualitative aspects of erythrocytes are also impaired in CKD, including loss of deformability and shortened life-span. Therefore, monitoring Hb alone could potentially fail to reveal pathological changes in erythrocytes. Focusing on erythrocyte quality in CKD may lead to more effective anemia therapy with C.E.R.A.. A CKD rat model was induced by uninephrectomy followed by anti-Thy1.1 antibody injection. From 5 weeks after the operation, C.E.R.A. (0.6 μg/kg) or vehicle was administered every 2 weeks. Erythrocyte deformability was quantified with ektacytometry and erythrocyte turnover was estimated by biotin labeling. Intracellular calcium level was assessed by Fluo-3/AM.. Erythrocyte deformability progressively declined in CKD rats. Furthermore, erythrocyte turnover in the circulation drastically accelerated in CKD rats. With administration of C.E.R.A. at a dose sufficient to adequately control Hb, deterioration of erythrocyte deformability and turnover in CKD rats were significantly improved. Intracellular calcium, which plays a pivotal role in the mediation of erythrocyte quality, was significantly increased in CKD and was normalized by C.E.R.A.. C.E.R.A. treatment exerted a favorable effect not only on anemia but also on the improvement of erythrocyte quality. C.E.R.A. administered for the treatment of CKD-associated anemia may confer therapeutic benefits on erythrocytes.

Topics: Anemia; Animals; Erythrocytes; Erythropoietin; Male; Polyethylene Glycols; Rats; Rats, Inbred F344; Renal Insufficiency, Chronic; Treatment Outcome

Topics: Animals; Cytokines; Erythropoietin; Humans; Iron; Mice; Muscle Proteins; Peptide Hormones; Renal Insufficiency, Chronic

The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD).. We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results.. At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001).. Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Assessment; Treatment Outcome

Chronic kidney disease (CKD) is a global health problem with an increasing prevalence worldwide. Anemia is one of its consistent and severe hematological complications although its mechanism is not fully elucidated. The primary defect could manifest as serum erythropoietin (sEPO) deficiency or EPO resistance. We set out to determine the erythropoietic response to anemia of patients with CKD and its relationship with their iron status in a cross-sectional descriptive study of 91 patients in various stages of CKD. Materials and Methods: Soluble transferrin receptor (sTfR), sEpo, and serum ferritin levels were determined using ELISA method (Diagnostic Automation Inc and WKEA med supplies corp.). Data generated were analyzed using Epi Info version 3.5.3 and level of statistical significance was set at ≤0.05. Results: Participants comprised of 50 females (54.9%) and 41 (45.1%) males with an overall mean age of 47 ± 15 years. The major causes of CKD were hypertension (HTN) (50.54%), diabetes mellitus (DM) (6.59%), and HTN + DM (19.78%). The mean hemoglobin (Hb) concentration of the participants was 10.97 ± 2.28 g/dl; the red cell indices were within normal ranges except for Red cell distribution width-Coefficient of variation (%) which was elevated (16.29%). The mean serum ferritin, sTfR, and sEpo were 70.58 ± 46.44 ng/ml (interquartile range [IQR] 82.00), 22.9 ± 49.7 ng/ml (IQR 15.00), and 12.49 ± 33.47 IU/L (IQR 6.00), respectively, with a high variance. Serum ferritin and sTfR are consistently low across the stages of CKD (range between 54.54 ng/ml and 88.64 ng/ml), but sEPO for stage 3 and 4 showed a 2-fold increase when compared to normal level at Hb 10.97 g/dl (29.54 IU/L and 38.83 IU/L, respectively). Correlation between sTfR and sEpo (r. In contrast to some existing literature, this study has demonstrated that EPO resistance and iron deficiency contributes to anemia in CKD and serum ferritin can be used to assess the iron level of dialysis naïve CKD patients at every stage of the disease.

Topics: Anemia; Cross-Sectional Studies; Erythropoiesis; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Nigeria; Renal Dialysis; Renal Insufficiency, Chronic

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and treatment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not predictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of iron in vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia.

Topics: Anemia; Biological Transport, Active; Bone Marrow; Cation Transport Proteins; Computational Biology; Epoetin Alfa; Erythrocytes; Erythropoietin; Hepcidins; Humans; Iron; Iron-Dextran Complex; Liver; Models, Biological; Mononuclear Phagocyte System; Renal Insufficiency, Chronic; Transferrin

Anemia commonly occurs in people with chronic kidney disease (CKD) and is associated with poor clinical outcomes. The management of patients with anemia in CKD is challenging, due to its severity, frequent hypo-responsiveness to treatment with erythropoiesis stimulating agents (ESA) and common hemoglobin cycling. Nonlinear dose-response curves and long delays in the effect of treatment on red blood cell population size complicate predictions of hemoglobin (Hgb) levels in individual patients. A comprehensive physiology based mathematical model for erythropoiesis was adapted individually to 60 hemodialysis patients treated with ESAs by identifying physiologically meaningful key model parameters from temporal Hgb data. Crit-Line® III monitors provided non-invasive Hgb measurements for every hemodialysis treatment. We used Hgb data during a 150-day baseline period together to estimate a patient's individual red blood cell lifespan, effects of the ESA on proliferation of red cell progenitor cells, endogenous erythropoietin production and ESA half-life. Estimated patient specific parameters showed excellent alignment with previously conducted clinical studies in hemodialysis patients. Further, the model qualitatively and quantitatively reflected empirical hemoglobin dynamics in demographically, anthropometrically and clinically diverse patients and accurately predicted the Hgb response to ESA therapy in individual patients for up to 21 weeks. The findings suggest that estimated model parameters can be used as a proxy for parameters that are clinically very difficult to quantify. The presented method has the potential to provide new insights into the individual pathophysiology of renal anemia and its association with clinical outcomes and can potentially be used to guide personalized anemia treatment.

Topics: Aged; Algorithms; Anemia; Biomarkers; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Models, Theoretical; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is a known driver for hypoxia inducible factor (HIF) which leads to increased renal erythropoietin (EPO) synthesis. Bone marrow (BM) EPO receptor (EPOR) signals are transduced through a JAK2-STAT5 pathway. The origins of anemia of chronic kidney disease (CKD) are multifactorial, including impairment of both renal EPO synthesis as well as intestinal iron absorption. We investigated the HIF- EPO- EPOR axis in kidney, BM and proximal tibia in anemic juvenile CKD rats.. CKD was induced by 5/6 nephrectomy in young (20 days old) male Sprague-Dawley rats while C group was sham operated. Rats were sacrificed 4 weeks after CKD induction and 5 minutes after a single bolus of IV recombinant human EPO. An additional control anemic (C-A) group was daily bled for 7 days.. Hemoglobin levels were similarly reduced in CKD and C-A (11.4 ± 0.3 and 10.8±0.2 Vs 13.5±0.3 g/dL in C, p<0.0001). Liver hepcidin mRNA was decreased in CA but increased in CKD. Serum iron was unchanged while transferrin levels were mildly decreased in CKD. Kidney HIF2α protein was elevated in C-A but unchanged in CKD. Kidney EPO protein and mRNA levels were unchanged between groups. However, BM EPO protein (which reflects circulating EPO) was increased in C-A but remained unchanged in CKD. BM and proximal tibia EPOR were unchanged in C-A but decreased in CKD. Proximal tibial phospho-STAT5 increased after the EPO bolus in C but not in CKD.. Compared to blood loss, anemia in young CKD rats is associated with inappropriate responses in the HIF-EPO-EPO-R axis: kidney HIF2α and renal EPO are not increased, BM and bone EPOR levels, as well as bone pSTAT5 response to EPO are reduced. Thus, anemia of CKD may be treated with additional therapeutic avenues beyond iron and EPO supplementation.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Bone Marrow; Disease Models, Animal; Erythropoietin; Hepcidins; Kidney; Liver; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency, Chronic; RNA, Messenger; Signal Transduction; STAT5 Transcription Factor

Anemia is an inevitable complication of hemodialysis, and the primary cause is erythropoietin deficiency. After diagnosis, treatment begins with an erythropoiesis-stimulating agent (ESA). However, some patients remain anemic even after receiving this medication. This study aimed to investigate the factors associated with resistance to recombinant human erythropoietin therapy with epoetin alfa (αEPO). We performed a prospective, longitudinal study of hemodialysis patients receiving treatment with αEPO at our reference hospital from July 2015 to June 2016. Clinical data was collected, and the response to αEPO treatment was evaluated using the erythropoietin resistance index (ERI). The ERI was defined as the weekly weight-adjusted αEPO dose (U/kg per week)/hemoglobin level (g/dL). A longitudinal linear regression model was fitted with random effects to verify the relationships between clinical and laboratory data and ERI. We enrolled 99 patients (average age, 45.7 (±17.6) years; male, 51.5%; 86.8% with hypertension). The ERI showed a significant positive association with serum ferritin and C-reactive protein, percentage interdialytic weight gain, and continuous usage of angiotensin receptor blocker (ARB) hypertension medication. The ERI was negatively associated with serum iron and albumin, age, urea reduction ratio, and body mass index. Our findings indicate that resistance to αEPO was related to a low serum iron reserve, an inflammatory state, poor nutritional status, and continuous usage of ARBs.

Topics: Adult; Anemia; Body Mass Index; Drug Resistance; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iron; Linear Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Reference Values; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome

Cognitive dysfunction is reported to be a major cause of morbidity in chronic kidney disease (CKD). The senile plaques (SPs) in the brain are one of the most pathophysiological characteristics of cognitive dysfunction and its major constituent amyloid β (Aβ) released from amyloid precursor protein (APP) by β (BACE1) and γ (presenilin 1) secretases . Platelets contain more than 95% of the circulating APP and implicate as a candidate biomarker for cognitive decline. Recombinant human erythropoietin (rHuEPO) is a standard therapy for anemia in CKD and also acts as a neuroprotective agent. The aim of the study is to determine the impact of rHuEPO therapy on platelet APP processing in CKD with Cognitive Dysfunction.. A total of 60 subjects comprising of 30 CKD without cognitive dysfunction and 30 CKD with cognitive dysfunction based on neuropsychological assessment. APP, BACE1, Presenilin 1, ADAM 10 (α secretase) and Aβ expressions in platelets were determined by western blotting and lipid peroxidation (LPO) in platelet rich plasma (PRP) was done by spectrophotometrically. The parameters were statistically compared with Alzheimer's disease (AD), Normocytic normochromic anemic and healthy subjects.. Significantly (p < 0.05) decreased APP, ADAM 10 while increased BACE1, Presenilin 1, Aβ and LPO were observed in CKD with cognitive dysfunction like AD subjects compared to other groups. The parameters were reassessed in CKD with cognitive dysfunction subjects after rHuEPO (100 IU/ kg, weekly twice, 6 months) therapy. All the parameters were retrieved significantly (p < 0.05) along with improved neuropsychological tests scoring after rHuEPO therapy.. This study demonstrated that rHuEPO is an effective neuroprotective agent in the context of CKD associated cognitive dysfunction and proved its clinical usefulness.

Topics: ADAM10 Protein; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Blood Platelets; Brain; Cognitive Dysfunction; Erythropoietin; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Pilot Projects; Presenilin-1; Proteins; Recombinant Proteins; Renal Insufficiency, Chronic; Young Adult

Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.

Topics: Activating Transcription Factor 4; Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Erythropoietin; Gene Knockdown Techniques; Hep G2 Cells; Humans; Kidney; Laser Capture Microdissection; Male; Mice; Mice, Inbred C57BL; Palmitates; Renal Insufficiency, Chronic; RNA, Small Interfering; Unfolded Protein Response

Decreased production of erythropoietin (EPO) is a major cause of anemia associated with chronic kidney disease (CKD). Treatment with recombinant human EPO (rHuEPO) improves patients' quality of life and survival; however, there is a marked variability in response to rHuEPO. At present, no available laboratory test is capable of evaluating responsiveness to EPO treatment. The aim of the present study was to use an in vitro bioassay to estimate the effect of uremic environment on EPO-dependent erythroid cell proliferation.. EPO-dependent human erythroleukemia cells (UT-7) were incubated with exogenous EPO (2 u/ml) and sera obtained from 60 pediatric patients (aged 1-23 years). Three groups were studied: (1) 12 children on dialysis (4 peritoneal, 8 hemodialysis); (2) 28 patients with CKD 1-5 (not on dialysis), and (3) 20 healthy children.. Sera from dialysis patients inhibited UT-7 cell growth compared to the CKD group and healthy controls at 48 h (p = 0.003 and p = 0.04, respectively) and 72 h of culture (p = 0.02 and p = 0.07, respectively). In 18 patients treated with rHuEPO, a significant inverse correlation was found between the EPO resistance index and cell proliferation at 48 h (p = 0.007, r = - 0.63) and 72 h (p = 0.03, r = - 0.52).. Our findings support the presence of erythropoiesis inhibitory substances in uremic sera. EPO/EPO-R-dependent mechanisms may play a role in inhibiting erythropoiesis. The in vitro bioassay described herein may serve as an indicator of rHuEPO responsiveness which may encourage further investigation of underlying mechanisms of EPO resistance.

Topics: Adolescent; Adult; Anemia; Biological Assay; Cell Line, Tumor; Child; Child, Preschool; Drug Resistance; Erythropoiesis; Erythropoietin; Female; Humans; Infant; Male; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Uremia; Young Adult

Topics: Anemia; Animals; Dihydropyridines; Disease Models, Animal; Enzyme Assays; Enzyme Inhibitors; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Inhibitory Concentration 50; Macaca fascicularis; Mice; Mice, Inbred BALB C; Pyridines; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic

Renal anemia is common among chronic kidney disease (CKD) patients, and is mainly caused by inadequate erythropoietin (EPO) production from kidneys due to dysfunction of intracellular hypoxia-inducible factor (HIF) signaling in renal EPO-producing cells. We have previously shown that indoxyl sulfate (IS), a representative protein-bound uremic toxin accumulated in the blood of CKD patients, inhibits hypoxia-induced HIF activation and subsequent EPO production through activation of aryl hydrocarbon receptor (AHR). In this study, we further investigated the effects of other protein-bound uremic toxins on HIF-dependent EPO expression using EPO-producing HepG2 cells. We found that indoxyl glucuronide (IG) and IS, but not p-cresyl sulfate, phenyl sulfate, 3-indoleacetic acid or hippuric acid, inhibited hypoxia mimetic cobalt chloride-induced EPO mRNA expression. Furthermore, IG at concentrations similar to the blood levels in CKD patients inhibited the transcriptional activation of HIF induced by both cobalt chloride treatment and hypoxic culture. IG also induced CYP1A1 mRNA expression and nuclear translocation of AHR protein, indicating that IG activates AHR signaling. Blockade of AHR by a pharmacological antagonist CH-223191 abolished the IG-induced inhibition of HIF activation. Collectively, this study is the first to elucidate the biological effects of IG to inhibit HIF-dependent EPO production through activation of AHR. Our data suggests that not only IS but also IG contributes to the impairment of HIF signaling in renal anemia.

Topics: Cell Survival; Cytochrome P-450 CYP1A1; Erythropoietin; Gene Expression Regulation; Glucuronates; Hep G2 Cells; Humans; Indican; Indoles; Protein Binding; Receptors, Aryl Hydrocarbon; Renal Insufficiency, Chronic; Signal Transduction; Transcriptional Activation; Uremia

The objective of the study was to examine overall anemia management trends in non-dialysis patients with chronic kidney disease (CKD) from 2006 to 2015, and to evaluate the impact of Trial to Reduced Cardiovascular Events with Ananesp Therapy (TREAT)'s study results (October 2009) and the US Food and Drug Administration (FDA)'s (June 2011) safety warnings and guidelines on the use of ESA therapy in the current treatment of anemia.. A retrospective cohort analysis of anemia management in CKD patients using Truven MarketScan Commercial and Medicare Supplemental databases was conducted. Monthly rates and types of anemia treatment for post-TREAT and post-FDA safety warning periods were compared to pre-TREAT period. Anemia management included ESA, intravenous iron, and blood transfusion. A time-series analysis using Autoregressive Integrated Moving Average (ARIMA) model and a Generalized Estimating Equation (GEE) model were used.. Between 2006 and 2015, CKD patients were increasingly less likely to be treated with ESAs, more likely to receive intravenous iron supplementation, and blood transfusions. The adjusted probabilities of prescribing ESAs were 31% (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.67-0.71) and 59% (OR = 0.41, 95% CI: 0.40, 0.42) lower in the post-TREAT and post-FDA warning periods compared to pre-TREAT period. The probability of prescribing intravenous iron was increased in the post-FDA warning period (OR = 1.11, 95% CI: 1.03-1.19) although the increase was not statistically significant in the post-TREAT period (OR = 1.03, 95% CI: 0.94-1.12). The probabilities of prescribing blood transfusion during the post-TREAT and post-FDA warning periods increased by 14% (OR = 1.14, 95% CI: 1.06-1.23) and 31% (OR = 1.31, 95% CI: 1.22-1.39), respectively. Similar trends of prescribing ESAs and iron supplementations were observed in commercially insured CKD patients but the use of blood transfusions did not increase.. After the 2011 FDA safety warnings, the use of ESA continued to decrease while the use of iron supplementation continued to increase. The use of blood transfusions increased significantly in Medicare patients while it remained stable in commercially insured patients. Results suggest the TREAT publication had effected treatment of anemia prior to the FDA warning but the FDA warning solidified TREAT's recommendations for anemia treatment for non- dialysis dependent CKD patients.

Topics: Adult; Aged; Anemia; Blood Transfusion; Cohort Studies; Darbepoetin alfa; Databases, Factual; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; United States; Young Adult

Anemia is a common complication in chronic kidney disease (CKD) patients receiving hemodialysis. The effect of high-flux dialysis (HFD) on anemia remains unclear. This prospective study aimed to evaluate the effect of HFD on anemia, and the potential of soluble transferrin receptor (sTfR) as a marker of iron status and erythropoiesis in CKD patients on hemodialysis. Forty patients, who switched from conventional low-flux dialysis to HFD for 12 months, were enrolled in this study. The levels of sTfR, hemoglobin (Hb), iron, and nutritional markers, as well as the dose of recombinant human erythropoietin (rhEPO) and use of chalybeate were determined at 0, 2, 6, and 12 months after starting HFD. HFD significantly increased the hemoglobin level and reduced sTfR level in CKD patients (p < 0.05). In addition, significant decreasing linear trends were observed for rhEPO dosage and chalybeate use (p < 0.05). The level of sTfR was positively correlated with the percentage of reticulocytes (RET%), rhEPO dose, and chalybeate use, while it was negatively correlated with Hb levels and total iron-binding capacity results (all p < 0.05). A univariate generalized estimating equation (GEE) model showed that the Hb level, RET%, rhEPO dose, and chalybeate use were the variables associated with sTfR levels. A multivariate GEE model showed that the time points when hemodialysis was performed were the variables associated significantly with sTfR levels. Overall, our findings suggest that HFD can effectively improve renal anemia in hemodialysis patients, and sTfR could be used as a marker of erythropoiesis in HFD patients.

Topics: Adult; Aged; Algorithms; Biomarkers; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Iron; Male; Middle Aged; Prospective Studies; Receptors, Transferrin; Renal Dialysis; Renal Insufficiency, Chronic; Reticulocytes

Hyporesponse to erythropoietin is a common problem seen in around 5-10% of patients. Recently the focus from these remediable factors has been shifted to the non-modifiable innate factors i.e polymorphism of ACE and IL-1B gene and studies have shown that DD genotype and IL-1B CC genotype have lower erythropoietin requirement. The aim of our study was to evaluate the role of ACE and IL-1B gene polymorphisms in erythropoietin hyporesponse in CKD patients with anemia.. A total of 50 patients were selected. After taking pre-informed written consent, they were segregated into two groups, group A and B with 25 patients in each group. Group A included CKD stage III-IV patients and Group B included CKD stage V patients who were on regular maintenance. All patients were given erythroepoietin and response was monitored using erythropoietin resistance index (ERI). Genotyping of ACE and IL-1B genes were done and serum levels of ACE and IL-1B were measured. Mean values of ERI were compared between different genotype subgroups and analysed using binary regression analysis.. The study group included 6 patients with diabetic nephropathy and out of these 4(66.6%) had DD genotype. On comparing the effect of ACE polymorphism on ERI levels it was seen that the mean ERI values in DD subgroup were significantly lower (16.97±5.35, 21.88±6.25, 22.69±8.35 at 1,3 and 5th month) as compared to ID (18.16±3.39, 24.17±3.66, 32.74±9.95 and II (20.73±5.17, 27.74±7.30, 41.08±13.83 U/Kg/g/dL). In the case of IL-1B the mean ERI values were lowest in the TT subgroup (16.46±4.45, 21.96±5.77,23.98±8.48) as compared to CC (19.49 ±5.62,25.46±7.07, 33.59±12.61) and CT (18.12±4.27,24.14±5.70, 31.89±13.83 U/Kg/g/dL). The mean serum values of ACE were in a decreasing trend i.e DD> ID> II (238.05 ± 52.46, 194.73±50.28 and 162.99±39.71 ng/ml, (p < 0.05). The mean serum values of IL1B in CC, CT and TT were 23.24±28.77, 18.32±16.25, 23.34±13.83 pg/ml (p>0.05).. D allele positively affected the serum ACE level but there was no association between IL-1B genotype and its levels. ACE gene polymorphism has an important role in determining the response to EPO and progression of CKD. Pre-treatment screening for genotype may help in predicting the patients at risk and poor responders.

Topics: Adult; Anemia; Drug Resistance; Erythropoietin; Female; Genotype; Hematinics; Humans; Interleukin-1beta; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renal Insufficiency, Chronic

The role of vitamin D deficiency and inflammation levels in renal anemia has been documented. However, no study is available in India where the role of vitamin D supplementation in patients with hyporesponsiveness to increased doses of erythropoietin is available. Hence this study.. This study was conducted on 50 adult patients of CKD, on regular, twice weekly hemodialysis. It included 38 cases in group A with deficient serum vitamin D levels (<30 ng/ml) and 12 cases in group B with sufficient vitamin D levels (>30 ng/ml). Both groups of cases were receiving erythropoietin in a dose of 4000 I.U. subcutaneously twice weekly following dialysis and had failed to show rise in hemoglobin (Hb) >1gm/dl after one month, hence erythropoietin was increased to 6000 I.U. Group A was given additional vitamin D in a dose of 60000 I.U. orally, once a week for next three months along with erythropoietin 6000 I.U. where as Group B served as control. Hematological and renal parameters, ESR, high sensitivity C reactive protein (HsCRP) and serum ferritin were estimated at baseline and then at one monthly intervals for next four months. Parathyroid hormone (iPTH), serum B12, folic acid and vitamin D (25OHD3) were measured at the start and end of the study only. Erythropoietin resistance index (ERI) was calculated to evaluate dose response.. Basal ERI, HsCRP and ESR and serum ferritin were raised in both the groups. At the end of four months, there was a significant increase in the Hb and hematocrit (Hct) (p<.001) and a significant fall in ERI, ESR, HsCRP, serum ferritin and iPTH (p<.001) in group A. Group B, also had a significant increase in the hemoglobin and hematocrit (p<.001) and decrease in ERI, ESR, HsCRP, serum ferritin and iPTH which was not significant. Basal vitamin D and ERI had a positive and insignificant correlation (r=0.05; p=0.756) in group A where as a negative and insignificant correlation was observed between them at the end of four months (r= -0.195; p >0.05).. vitamin D play an important role in reducing inflammation and thereby in the cure of anemia in EPO hyporesponsive CKD patients and needs to be supplemented, if deficiency is found.

Topics: Anemia; C-Reactive Protein; Drug Resistance; Erythropoietin; Female; Ferritins; Hematinics; Hematocrit; Hemoglobins; Humans; Male; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency

We compared the hemoglobin-maintaining effects between continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) in patients with chronic kidney disease (CKD) during the 3 months before dialysis initiation.. This study was conducted with 37 CERA-administered patients and 26 DA-administered patients who had initiated dialysis at a participating facility between January 2012 and December 2014. We investigated clinical laboratory data 3 months before and at dialysis initiation, and compared these data between the CERA and DA groups.. Our results suggest that CERA may be more effective than DA in maintaining hemoglobin levels in patients with CKD during 3 months before dialysis initiation.

Topics: Aged; Aged, 80 and over; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Reticulocyte Count; Time Factors

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice

Topics: Aged; Amidohydrolases; Anemia; Animals; Arginine; Cytokines; Drug Resistance; Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Gene Expression; Hematinics; Hematocrit; Hemoglobins; Humans; Male; Mice; Middle Aged; Muscle Proteins; Nephrectomy; Plasma; Receptors, Erythropoietin; Renal Insufficiency, Chronic

The clinical importance of serum hepcidin in non-dialysis chronic kidney disease (CKD) patients is unclear. The database of a large-scale multicentre prospective study in Korea of 2238 patients enrolled from 2011-2016 was analysed. After excluding patients with missing serum hepcidin (n = 125) and haemoglobin (n = 23) levels, the study included 2090 non-dialysis CKD patients. Markers of inflammation and iron status were positively associated with serum hepcidin level, regardless of CKD stage. However, estimated glomerular filtration rate was inversely associated with serum hepcidin level, particularly in patients with CKD stages 3b-5 but not in those with CKD stages 1-3a. Use of erythropoiesis-stimulating agents was associated with increased serum hepcidin levels, particularly in patients with CKD stages 3b-5 but not in those with CKD stages 1-3a, and serum hepcidin levels positively correlated with the dose of erythropoiesis-stimulating agent. These findings suggest that serum hepcidin may be a uremic toxin and play an important role in erythropoietin resistance. However, future prospective studies are needed to confirm our results.

Topics: Adult; Aged; C-Reactive Protein; Erythropoiesis; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hepcidins; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Republic of Korea

Anemia is a frequent complication of Chronic Kidney Disease CKD commonly found in chronic haemodialysis patients. Patients management is mainly based on erythropoietin administration and iron supplementation. This study aimed to evaluate the management of chronic hemodialysis patients with anemia in the Department of Nephrology and Hemodialysis at the University Hospital Point G in Mali.. We conducted a cross-sectional study from 1 to 31 August 2016.. 63 patients out of a total of 174 participants were selected, 34 men and 29 women with a sex-ratio of 1.17 in favor of men. The average age of patients was 48,79 years ±11.59, the average duration of hemodialysis treatment time was 3,77years±2.6. Hospitalization rate for anemia in our dialysis patients was 84,12%. 92.1% of patients required blood transfusion, with an annual average of 5,81 blood bags ±5.91. 87.3% of cases required iron supplementation. Mean ferritin concentration and TSC were 1245 ng/ml±629,52 and 46,16%±19.12 respectively. Occasional administration of EPO doses not exceeding the 4000IU was reported by 79.4% of patients. The main difficulty in using EPO was its cost (74.6%). HCV infection was found in 60.1% of patients who were assessed.. The management of chronic dialysis patients with anemia should be integrated into the framework of the national health policy.

Topics: Adolescent; Adult; Aged; Anemia; Blood Transfusion; Cross-Sectional Studies; Erythropoietin; Female; Ferritins; Hematinics; Hospitalization; Hospitals, University; Humans; Iron Compounds; Male; Mali; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

To assess the safety and immunogenicity of subcutaneous (SC) HX575 (epoetin-α) in dialysis- and nondialysis-dependent adult patients with chronic kidney disease (CKD).. Open-label, single-arm, multicenter study in patients (n = 416) from Germany, Italy, Poland, Romania, Russia, Turkey, and Ukraine.. Mean (standard deviation (SD)) age was 52.3 (15.8) years, all patients were Caucasian, and similar proportions were male/female. 250 patients (60.1%) were erythropoiesis-stimulating agent (ESA)-naïve, and 166 (39.9%) were receiving ESA maintenance therapy at study start; mean (SD) on-study treatment duration with HX575 was 43.4 (15.8) weeks and 45.3 (13.7) weeks, respectively. Binding antierythropoietin (EPO) antibodies were detected by radioimmunoprecipitation (RIP) assay in 7 patients (1.7%; incidence 0.019); 5 of these were ESA-naïve at study entry. No patient developed neutralizing antibodies as determined in a cell-based epoetin neutralizing assay. Of the 7 patients with a positive binding anti-EPO RIP assay, 4 tested negative at later time points while continuing HX575 treatment. Three patients had low titers of anti-EPO antibodies at the last study assessment. There were no clinical signs of immunogenicity or hypersensitivity.. SC HX575 was effective for correcting and maintaining correction of anemia, and the mean weekly dose remained stable over time.
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Topics: Adult; Aged; Anemia; Epoetin Alfa; Erythropoietin; Europe; Female; Hematinics; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and is frequently associated with decreased physical component of quality of life, as well as adverse cardiovascular events. Current treatment methods for renal anemia are mostly population-based approaches treating individual patients with a one-size-fits-all model. However, FDA recommendations stipulate individualized anemia treatment with precise control of the hemoglobin concentration and minimal drug utilization. In accordance with these recommendations, this work presents an individualized drug dosing approach to anemia management by leveraging the theory of optimal control.. A Multiple Receding Horizon Control (MRHC) approach based on the RBF-Galerkin optimization method is proposed for individualized anemia management in CKD patients. Recently developed by the authors, the RBF-Galerkin method uses the radial basis function approximation along with the Galerkin error projection to solve constrained optimal control problems numerically. The proposed approach is applied to generate optimal dosing recommendations for individual patients.. Performance of the proposed approach (MRHC) is compared in silico to that of a population-based anemia management protocol and an individualized multiple model predictive control method for two case scenarios: hemoglobin measurement with and without observational errors. In silico comparison indicates that hemoglobin concentration with MRHC method has less variation among the methods, especially in presence of measurement errors. In addition, the average achieved hemoglobin level from the MRHC is significantly closer to the target hemoglobin than that of the other two methods, according to the analysis of variance (ANOVA) statistical test. Furthermore, drug dosages recommended by the MRHC are more stable and accurate and reach the steady-state value notably faster than those generated by the other two methods.. The proposed method is highly efficient for the control of hemoglobin level, yet provides accurate dosage adjustments in the treatment of CKD anemia.

Topics: Anemia; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Hemoglobins; Humans; Models, Theoretical; Renal Insufficiency, Chronic

This study was planned to evaluate the effect of short term intravenous ascorbic acid on reducing ferritin and erythropoietin resistance in patients of chronic kidney disease (CKD) on maintenance haemodialysis (MHD).. Forty adult patients [20 patients in group A with increased serum ferritin level (>500 ng/ml), transferrin saturation (TSAT) ≤20% and 20 patients in group B with normal serum ferritin level (<200 ng/ml), TSAT ≤20%] of end stage renal disease (ESRD) with erythropoietin hyporesponsiveness undergoing maintenance hemodialysis were included in the study. Group A was given intravenous (i.v.) ascorbic acid in a dose of 500 mg once a week after each 4 hours session of dialysis for 3 weeks in a month (total 1500 mg/month), for a period of 3 months along with erythropoietin 6000 IU subcutaneous (S/C) twice weekly without iron therapy. Group B was given erythropoietin (6000 IU S/C twice weekly after each hemodialysis) and intravenous (IV) iron 100 mg/week for 3 months. Hematological and renal investigations, erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (HsCRP), serum ferritin and TSAT were done at baseline and then one monthly intervals for three months whereas intact parathyroid hormone (iPTH) was measured at the start and end of the study.. At the end of 3 months of study, in group A, Hemoglobin (Hb) and TSAT significantly increased while ferritin, HsCRP and erythropoietin resistance index (ERI) decreased significantly. In group B, the increase in Hb and TSAT were not significant statistically while ferritin increased significantly and fall in HsCRP and ERI were not significant statistically. The mean rise in Hb between subsequent months was higher in group A as compared to group B.. Short term i.v ascorbic acid could be a new successful adjuvant in reducing ferritin and erythropoietin resistance and enhancing Hb and TSAT in CKD patients on MHD.

Topics: Antioxidants; Ascorbic Acid; Drug Resistance; Erythropoietin; Female; Ferritins; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Adult; Anemia; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Male; Middle Aged; Registries; Renal Dialysis; Renal Insufficiency, Chronic; United Kingdom

The aim of this study was to investigate the expression pattern of CD55 and CD59 on red blood cells (RBCs) in anemic chronic kidney disease (CKD) patients, and factors that might influence their expression.. Nighty-one adult anemic CKD patients and 80 healthy controls (HCs) were enrolled. Anemic CKD patients were divided into 3 subgroups based on receiving erythropoietin and renal replacement therapies. Flow cytometric analysis of CD55 and CD59 expression was performed on RBCs from blood samples obtained from CKD patients and HCs.. CD59 deficiency was significantly higher among CKD patients than HCs (n = 68, 74.7%, vs. n = 13, 16.3%, respectively; p < 0.001). The median proportions of CD55- and CD59-deficient RBCs in CKD patients were significantly higher compared to HCs (0.34 vs. 0.15, and 4.3 vs. 2.0, p < 0.001 and p < 0.001, respectively). The mean fluorescence intensity (MFI) of CD55 and CD59 expression was significantly lower in CKD patients compared to HCs (1.2 vs. 2.8, and 17.0 vs. 20.3, p < 0.04 and p < 0. 001, respectively). The hemoglobin level was inversely correlated with the proportions of CD55- and CD59-deficient RBCs (r = -0.37, p < 0.001, and r = -0.22, p < 0.02, respectively). The number of CD59-deficient patients was significantly different between the 3 subgroups of CKD patients (p = 0.001), and a significant difference was present in the MFI of CD55 and CD59 expression among the 3 subgroups (p = 0.04 and p = 0.03, respectively).. The expression pattern of CD55 and CD59 on RBCs is altered in anemic CKD patients, which could play a role in the pathogenesis of anemia in CKD.

Topics: Adult; Aged; Anemia; Biomarkers; CD55 Antigens; CD59 Antigens; Erythrocytes; Erythropoietin; Female; Flow Cytometry; Hemolysis; Humans; Male; Middle Aged; Renal Insufficiency, Chronic

Chronic kidney disease leads to dysfunction of renal erythropoietin-producing cells, resulting in a decrease in erythrocyte production. A decrease in oxygen delivery to vital organs due to anemia results in worse quality of life and is associated with poor prognosis of the patients. Treatment with human recombinant erythropoietin or its improved version of erythropoiesis-stimulating agent (ESA) with a longer half-life is effective. However, some patients show hyporesponsiveness to ESA. Hyporesponsiveness to ESA, which can be induced by factors such as inflammation and uremic toxins, is associated with poor prognosis. Production of erythropoietin in the kidney is regulated by a transcription factor, hypoxia-inducible factor (HIF). PHD regulates HIF activity, and recently developed PHD inhibitors need to be clinically used as drugs to ameliorate anemia in CKD by activating HIF.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor 1; Iron; Renal Insufficiency, Chronic

Erythropoietin (EPO) is a hormone that promotes proliferation, differentiation and survival of erythroid progenitors. EPO gene expression is regulated in a tissue-specific and hypoxia-inducible manner and is mainly restricted to renal EPO-producing cells after birth. Chronic kidney disease (CKD) confers high risk for renal anemia due to lower EPO production from injured kidneys. In transgenic reporter lines of mice, disruption of a GATA-binding motif within the Epo gene promoter-proximal region restores constitutive reporter expression in epithelial cells. Here, mitoxantrone and its analogues, identified as GATA factor inhibitors through high-throughput chemical library screenings, markedly induce EPO/Epo gene expression in epithelium-derived cell lines and mice regardless of oxygen levels. In contrast, mitoxantrone interferes with hypoxia-induced EPO gene expression in Hep3B cells. Cryptic promoters are created for the EPO/Epo gene expression in epithelial cells upon mitoxantrone treatment, and consequently, unique 5'-untranslated regions are generated. The mitoxantrone-induced aberrant transcripts contribute to the reporter protein production in epithelial cells that carry the reporter gene in the proper reading frame of mouse Epo gene. Thus, EPO production in uninjured adult epithelial cells may be a therapeutic approach for renal anemia in patients with CKD.

Topics: Anemia; Animals; Base Sequence; Cells, Cultured; CRISPR-Cas Systems; Epithelial Cells; Erythropoietin; GATA Transcription Factors; Gene Expression Regulation; Genes, Reporter; High-Throughput Screening Assays; Humans; Male; Mice; Mice, Inbred C57BL; Mitoxantrone; Promoter Regions, Genetic; Renal Insufficiency, Chronic; Topoisomerase II Inhibitors

The association between responsiveness to continuous erythropoietin-receptor activator (CERA) and renal survival in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) is uncertain.. We performed a pooled analysis of individual patient-level data drawn from five clinical trials involving CERA administration. Based on the responsiveness to CERA, patients were classified into poor- or good-response groups. Primary endpoints were defined as the initiation of dialysis or a 30% decrease in the estimated glomerular filtration rate (eGFR) from baseline. We set the landmark time point at 12 weeks after the start of CERA, from which we evaluated the time to the first renal event. The cumulative renal survival rates were calculated for each group using the Kaplan-Meier method. The adjusted hazard ratio was calculated using a stratified Cox regression model.. Of 408 patients, 226 were analyzed. Haemoglobin levels and eGFRs were significantly lower in the poor-response group (n = 113) than in the good-response group (n = 113). Renal events occurred in 36.3% of the poor-response group and in 23.0% of the good-response group. The intergroup difference in renal survival rates was significant (log-rank test, P = 0.03) and the adjusted hazard ratio was 1.71 (95% confidence interval, 1.03-2.83), indicating an unfavorable outcome in the poor-response group.. Hyporesponsiveness to CERA was associated with poor renal survival, consistent with the results of the conventional erythropoiesis-stimulating agent (ESA). It is recommended that a randomized controlled trial on CERA use be performed in patients with NDD-CKD with ESA-hyporesponsive anaemia.

Topics: Aged; Anemia; Biomarkers; Clinical Trials as Topic; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney; Male; Middle Aged; Polyethylene Glycols; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

Topics: Adenine; Anemia; Animals; Blood Urea Nitrogen; Diet; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Hepcidins; Humans; Iron; Kidney Tubules; Mice; Mice, Inbred C57BL; Mice, Knockout; Renal Insufficiency, Chronic; Serum Amyloid A Protein

Anemia in chronic kidney disease (CKD) is a risk factor for cardiovascular diseases and is treated by long-acting erythropoiesis-stimulating agents (ESAs). Although the results of previous studies have shown that hemoglobin levels could not be maintained at the initiation of dialysis in CKD patients treated with recombinant human erythropoietin, it remains undetermined whether long-acting ESAs are effective in preventing the progression of anemia at the initiation of dialysis. In the present study, hemoglobin levels in 40 CKD patients treated with darbepoetin alfa (DA) and 15 CKD patients treated with a continuous erythropoietin receptor activator (CERA) were retrospectively compared during the 6 months period before the initiation of dialysis. Results showed that DA and CERA both maintained hemoglobin levels at around 10 g/dL from 6 months to 1 month before dialysis. However, hemoglobin levels at the initiation of dialysis significantly decreased to 9.1 ± 1.2 g/dL in the DA group and to 9.0 ± 1.0 g/dL in the CERA group. Although the total doses of ESAs used during the 6-month period were similar between the two groups, DA-treated CKD patients received subcutaneous injections more frequently than did patients treated with CERA. These results suggest that CKD patients require more intense ESA therapy to prevent a decline in hemoglobin levels at the initiation of dialysis, including those treated with long-acting ESAs. The results also raise the possibility that CERA is more useful than DA for reducing the number of injections during the pre-dialysis period.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors

The role of inflammation in the development and progression of chronic kidney disease (CKD) in cats is not well characterized. Hepcidin is a recently discovered acute-phase protein (APP) that plays an important role in iron metabolism and contributes to the development of anemia in humans with CKD.. To compare serum APP concentrations, iron status, and erythropoietin (EPO) concentrations in healthy cats and cats with naturally occurring CKD.. A total of 18 healthy control cats and 38 cats with CKD.. Prospective study. After complete physical examination and routine blood analysis, the following tests were performed: serum amyloid A (SAA), haptoglobin (HAP), EPO, serum iron and ferritin concentration as well as total iron-binding capacity (TIBC). Serum hepcidin-25 concentration was measured by ELISA kit designed for use in humans.. Mean SAA and hepcidin concentrations were significantly higher and mean total iron and TIBC were significantly lower in the CKD group (P < .05). There was a significant positive correlation between serum creatinine concentration (CRT) and 2 of the APPs (SAA and hepcidin; P < .05). Increases in SAA and hepcidin were associated with decreases in TIBC and hematocrit in the CKD group. Fourteen (37%) of the cats with CKD were anemic, and these cats had significantly lower TIBC (P < .05), suggesting a functional iron deficiency. There was no association between survival time and APP, iron status, or EPO concentrations.. Our data suggest that CKD in cats is associated with systemic inflammation and altered iron metabolism. With further validation in cats, hepcidin assays may help better characterize these relationships.

Topics: Acute-Phase Proteins; Anemia, Iron-Deficiency; Animals; Case-Control Studies; Cat Diseases; Cats; Erythropoietin; Female; Ferritins; Hematocrit; Hepcidins; Iron; Male; Prospective Studies; Renal Insufficiency, Chronic; Serum Amyloid A Protein

Exogenous replacement of erythropoietin (EPO) by recombinant human EPO has been considered a standard of care for the treatment of anemia in patients with chronic kidney disease for more than 20 years. Genetically engineered biologic proteins derived from human, animal, or microorganism sources are a major area of growth in modern medical care, accounting for one-third of new drug approvals in the past decade. Despite benefit to patients, the use of biologics comes at a significant cost, representing one of the fastest growing segments of strained healthcare budgets around the world.. Biosimilars, or biologic drugs that are designed to be highly similar to approved reference biologic drugs, have been available in Europe for more than 10 years with no unusual or unexpected effects compared to their reference biologics whose patents have expired. Given the success of the biosimilar approval pathway pioneered in Europe, it has served as a global reference for other regulatory authorities to establish and implement biosimilar licensure frameworks, including the United States (US), the largest pharmaceutical market in the world. Given 10 of the top 25 drugs sold in 2014 were biologics, and considering the rising costs of healthcare, biosimilars have the potential to become a significant part of the US market. Key Messages: For the nephrology community, the recent patent expiries for epoetin alfa (Epogen®, Amgen and Procrit®, Johnson & Johnson) have created the opportunity to develop biosimilar EPOs. And while no biosimilar in this therapeutic class is approved in the US, there are proposed biosimilars in development.

Topics: Anemia; Animals; Biosimilar Pharmaceuticals; Commerce; Drug Approval; Drug Industry; Epoetin Alfa; Erythropoiesis; Erythropoietin; Europe; Hematinics; History, 20th Century; History, 21st Century; Humans; Kidney; Kidney Diseases; Nephrology; Patient Safety; Recombinant Proteins; Renal Insufficiency, Chronic; United States

A common complication in patients undergoing peritoneal dialysis (PD) is a chronic inflammatory state and anemia that can be treating by recombinant human erythropoietin (rHuEPO). Higher required dose of rHuEPO could be expected in patients with higher cytokine levels. Additionally, it is known that peritoneal inflammation can be correlated with systemic inflammation and this could contribute to the compromised rHuEPO required dose in anemic patients with end stage renal disease (ESRD). Thus, the current study aimed to evaluate the association between levels of systemic and local interferon (IFN)-γ, interleukin (IL)-17 and other cytokines and the dose of rHuEPO used by patients undergoing PD for the correction of anemia.. Thirty-one patients under PD using rHuEPO were evaluated in this cross-sectional study. Plasma and dialysate levels of IL-2, IL-4, IL-6, IL-10, IL-17, tumour necrosis factor (TNF)-α and IFN-γ were determined using the Cytometric Bead Array TM kit (CBA; BD Bioscences, San Jose, CA). The relation between the levels of each cytokine levels and the tertiles of rHuEPO were plotted on box-plot graphics and then the medians of interleukins levels were compared by median comparison test. The significance level adopted was 5% and the analysis was performed by the softwares STATA (version 12.0) and GraphPad Prism 3.0.. The median of IL-17 and IFN-γ plasma levels were significant higher in the group with higher rHuEPO dosage. However, this association was not observed in the dialysate levels, as well as was not observed a relationship between the other plasma and dialysate cytokines evaluated in this study and the dose of rHuEPO.. Our study found increased IL-17 and IFN-γ plasma, but no dialysate levels, in patients receiving higher doses of rHuEPO, suggesting may exist a relationship between systemic inflammation of ESRD, and the necessary levels of rHuEPO for the correction of anemia in these patients.

Topics: Aged; Anemia; Cross-Sectional Studies; Cytokines; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Inflammation; Interferon-gamma; Interleukin-17; Male; Middle Aged; Peritoneal Dialysis; Renal Insufficiency, Chronic

Renal anemia complicated with chronic kidney disease is usually treated with erythropoiesis-stimulating agents (ESAs). However, few studies have compared the early response of hemoglobin (Hb) to different kinds of ESAs.. The effects of three types of ESAs-epoetin alfa or beta (EPO), darbepoetin alfa (DPO), and epoetin beta pegol (EPObp)-on renal anemia were followed in 416 pre-dialysis chronic kidney disease (CKD) patients. After the initial 12-week administration of ESAs, ΔHb/ESA dose/kg was calculated as an index of efficacy of each ESA. Furthermore, independent variables associated with ΔHb/ESA dose/kg (dependent variable) were determined using multiple linear regression analysis. The ten independent variables selected for analysis were: presence of diabetic nephropathy, estimated glomerular filtration rate (eGFR), Hb, albumin, iron (Fe), transferrin saturation (TSAT), ferritin, phosphate (P), intact parathyroid hormone (iPTH), and C-reactive protein.. The efficacy of DPO and EPObp were similar and higher than EPO. TSAT was most strongly correlated with ΔHb/EPO dose/kg in all three types of ESAs. Other significant independent factors were Hb, albumin, P, iPTH, and diabetic nephropathy in the EPO group, eGFR in the DPO group, and Fe in the EPObp group. The adjusted coefficient of determination (R (2)) ranged from 0.415 to 0.520 in the three ESA groups.. The study results suggest that TSAT is the best predictor of the initial 12-week responsiveness to ESA, irrespective of the type. Variables not investigated in this study also affect responsiveness to ESA in Japanese pre-dialysis CKD patients.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hematinics; Humans; Linear Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic

The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia.. In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high).. Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported.. The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Stroke; Young Adult

Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin-stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No large studies of which we are aware have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community-living older adults.. Erythropoietin concentration was measured in 2488 participants aged 70-79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease, stroke, mortality, and ≥ 30% decline in estimated glomerular filtration rate were examined using Cox proportional hazards and logistic regression over 10.7 years of follow-up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events, and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% confidence interval 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease, cardiovascular disease risk factors, kidney function, and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (P > 0.50). There were 330 incident coronary heart disease events, 161 strokes, 1112 deaths, and 698 outcomes of ≥ 30% decline in estimated glomerular filtration rate. Serum erythropoietin was not significantly associated with these outcomes.. Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.

Topics: Age Factors; Aged; Aging; Biomarkers; Body Composition; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Kidney; Logistic Models; Longitudinal Studies; Male; Multivariate Analysis; Prevalence; Prognosis; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Time Factors; United States; Up-Regulation

Renal erythropoietin-producing cells (REPCs) remain in the kidneys of patients with chronic kidney disease, but these cells do not produce sufficient erythropoietin in response to hypoxic stimuli. Treatment with HIF stabilizers rescues erythropoietin production in these cells, but the mechanisms underlying the decreased response of REPCs in fibrotic kidneys to anemic stimulation remain elusive. Here, we show that fibroblast-like FOXD1+ progenitor-derived kidney pericytes, which are characterized by the expression of α1 type I collagen and PDGFRβ, produce erythropoietin through HIF2α regulation but that production is repressed when these cells differentiate into myofibroblasts. DNA methyltransferases and erythropoietin hypermethylation are upregulated in myofibroblasts. Exposure of myofibroblasts to nanomolar concentrations of the demethylating agent 5-azacytidine increased basal expression and hypoxic induction of erythropoietin. Mechanistically, the profibrotic factor TGF-β1 induced hypermethylation and repression of erythropoietin in pericytes; these effects were prevented by 5-azacytidine treatment. These findings shed light on the molecular mechanisms underlying erythropoietin repression in kidney myofibroblasts and demonstrate that clinically relevant, nontoxic doses of 5-azacytidine can restore erythropoietin production and ameliorate anemia in the setting of kidney fibrosis in mice.

Topics: Animals; Azacitidine; Basic Helix-Loop-Helix Transcription Factors; Collagen Type I; Collagen Type I, alpha 1 Chain; DNA Modification Methylases; Erythropoietin; Fibrosis; Mice; Mice, Transgenic; Myofibroblasts; Pericytes; Receptor, Platelet-Derived Growth Factor beta; Renal Insufficiency, Chronic

Anemia of CKD seems to be related to impaired production of renal erythropoietin (Epo). The glycosylation pattern of Epo depends on the synthesizing cell and thus, can indicate its origin. We hypothesized that synthesis of Epo from nonkidney cells increases to compensate for insufficient renal Epo production during CKD. We determined plasma Epo levels and Epo glycosylation patterns in 33 patients with CKD before undergoing dialysis and nine patients with CKD undergoing dialysis. We compared these values with values obtained in healthy volunteers and other controls. Although patients with CKD before undergoing dialysis had median (interquartile range) Epo levels higher than those of healthy controls (13.8 IU/L; interquartile range, 10.0-20.7 IU/L versus 8.4 IU/L; interquartile range, 7.6-9.0 IU/L; P<0.01), these patients were moderately anemic (mean±SD; hemoglobin =118±17 g/L). Detected as the percentage of migrated isoforms (PMI), Epo glycosylation in patients with CKD before undergoing dialysis (PMI=36.1±11.7%) differed from that in healthy controls (PMI=9.2±3.8%; P<0.01) but not from that in umbilical cord plasma (PMI=53.9±10.6%; P>0.05), which contains mainly liver-derived Epo. Furthermore, glycosylation modification correlated with eGFR loss. These results suggest that patients with CKD maintain persistent Epo synthesis despite declining renal function, and this maintenance may result in part from increased liver Epo synthesis.

Topics: Aged; Erythropoietin; Female; Humans; Liver; Male; Renal Insufficiency, Chronic

The UK-based National Institute for Health and Care Excellence (NICE) has updated its guidance on iron deficiency and anemia management in chronic kidney disease. This report outlines the recommendations regarding iron deficiency and their rationale. Serum ferritin alone or transferrin saturation alone are no longer recommended as diagnostic tests to assess iron deficiency. Red blood cell markers (percentage hypochromic red blood cells, reticulocyte hemoglobin content, or reticulocyte hemoglobin equivalent) are better than ferritin level alone at predicting responsiveness to intravenous iron. When red blood cell markers are not available, a combination of transferrin saturation < 20% and ferritin level < 100ng/mL is an alternative. In comparisons of the cost-effectiveness of different iron status testing and treatment strategies, using percentage hypochromic red blood cells > 6% was the most cost-effective strategy for both hemodialysis and nonhemodialysis patients. A trial of oral iron replacement is recommended in people not receiving an erythropoiesis-stimulating agent (ESA) and not on hemodialysis therapy. For children receiving ESAs, but not treated by hemodialysis, oral iron should be considered. In adults and children receiving ESAs and/or on hemodialysis therapy, intravenous iron should be offered. When giving intravenous iron, high-dose low-frequency administration is recommended. For all children and for adults receiving in-center hemodialysis, low-dose high-frequency administration may be more appropriate.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Humans; Iron; Meta-Analysis as Topic; Practice Guidelines as Topic; Renal Insufficiency, Chronic

There is limited data showing that early treatment for anemia could prolong renal survival in non-dialysis chronic kidney disease (CKD) patients. We therefore investigated the relationship between hemoglobin (Hb) levels at initiation of epoetin beta therapy and renal outcome in non-dialysis CKD patients with anemia.. In this prospective, multi-center, observational study, non-dialysis CKD patients with anemia who were naïve to erythropoiesis-stimulating agents (ESAs) were divided into three groups based on their Hb levels at initiation of epoetin beta therapy (Group I: 10 ≤ Hb < 11 g/dL, Group II: 9 ≤ Hb < 10 g/dL, and Group III: Hb < 9 g/dL). The primary endpoint was time to first occurrence of any renal event. For the primary analysis, an inverse probability weighted Cox regression model was used to adjust time-dependent selection bias in the artificially censored data.. A total of 1113 patients were eligible for primary endpoint analysis. Risk of renal events was significantly higher in Group III compared with Group I (HR, 2.52; 95 % CI, 1.98-3.21; P < 0.0001); although not significant, the risk was also higher in Group II compared with Group I (HR, 1.48; 95 % CI, 0.91-2.40; P = 0.11).. Initiation of ESA therapy when Hb levels decreased below 11 g/dL but not below 10 g/dL could be more effective at reducing the risk of renal events in non-dialysis CKD patients with anemia compared with initiation of ESA therapy at below 9 g/dL or even 10 g/dL.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Renal Insufficiency, Chronic

Topics: Animals; Azacitidine; DNA Modification Methylases; Erythropoietin; Myofibroblasts; Pericytes; Renal Insufficiency, Chronic

Renal hypoplasia due to a congenitally reduced number of nephrons progresses to chronic kidney disease and may cause renal anemia, given that the kidneys are a major source of erythropoietin in adults. Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and develop CKD. This study assessed the renal function and hematologic changes in HPK rats from 70 to 210 d of age. HPK rats demonstrated deterioration of renal excretory function, slightly macrocytic erythropenia at all days examined, age-related increases in splenic hemosiderosis accompanied by a tendency toward increased hemolysis, normal plasma erythropoietin levels associated with increased hepatic and decreased renal erythropoietin production, and maintenance of the response for erythropoietin production to hypoxic conditions, with increased interstitial fibrosis at 140 d of age. These results indicate that increases in splenic hemosiderosis and the membrane fragility of RBC might be associated with erythropenia and that hepatic production of erythropoietin might contribute to maintaining the blood Hgb concentration in HPK rats.

Topics: Age Factors; Anemia; Animals; Biomarkers; Carrier Proteins; Disease Models, Animal; Disease Progression; Erythrocytes; Erythropoietin; Fibrosis; Genetic Predisposition to Disease; Hemolysis; Hemosiderosis; Iron; Kidney; Kidney Diseases; Male; Mutation; Osmotic Fragility; Phenotype; Rats; Rats, Inbred Strains; Renal Insufficiency, Chronic; Spleen

Erythropoiesis-stimulating agents (ESAs) play an important role in the management of anemia in patients with chronic kidney disease, but the goals cannot be reached in 5% to 10% of the patients despite high-dose ESA treatment. In case of ESA resistance, all causes of anemia encountered in the general population should be carefully reviewed. We present a patient examined for ESA resistance that was diagnosed with systemic lupus erythematosus and subsequently showed improvement of anemia with systemic corticosteroids.

Topics: Adult; Anemia; Erythropoietin; Female; Hematinics; Humans; Lupus Erythematosus, Systemic; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

A 38-year-old woman, obese (219 kg), diabetic, hypertensive, chronic kidney disease (CKD) stage 4, with low plasma albumin level (2.9 g dl(-1)) and marked proteinuria (22 g per day) was studied. Given the advanced-stage CKD with nephrotic proteinuria, we supplemented low-protein diet with high doses of a tailored essential amino acid mixture (AAs: 44 g per day) to improve weight reduction in the patient. After 20 months of conservative therapy, the patient lost 43 kg; despite two episodes of infection, albumin plasma levels increased up to 3.7 g per day. After a further 20 months of dialysis, the patient maintained a diet of 1800 kcal supplemented with 32 g of AAs and lost 47 kg, whereas both albumin (3.89±0.12 g dl(-1)) and C reactive protein returned to normal. During the follow-up period, anemia improved, erythropoietin was thus discontinued and insulin requirement decreased to 105 IU. This therapeutic option may be beneficial in advanced CKD patients with obesity and diabetes resulting from malnutrition.

Topics: Adult; Amino Acids, Essential; Amphetamine; Anemia; Body Mass Index; C-Reactive Protein; Diet, Protein-Restricted; Dietary Supplements; Energy Intake; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Obesity, Morbid; Patient Compliance; Proteinuria; Quality of Life; Renal Insufficiency, Chronic; Serum Albumin; Treatment Outcome; Waist Circumference

The most important cause of anemia in CKD is relative deficiency of erythropoietin (EPO) secretion from the diseased kidney and EPO therapy has become the standard treatment for anemia of CKD. However, some patients do not respond well to erythropoiesis stimulating agent (ESA), so-called ESA resistance. One of the most important causes of ESA resistance is chronic inflammation in hemodialysis (HD) patients. ESA hyporesponsiveness index (EHRI), calculated as the weekly dose of EPO divided by kilograms of body weight divided by the hemoglobin level, and has been considered useful to assess the EPO resistance. Neutrophil/lymphocyte (NLR) ratio and platelet/lymphocyte ratio (PLR) were also found to be associated with inflammation in HD patients. However, the relationship between NLR, PLR and EHRI has not been investigated before. HD patients underwent medical history taking, physical examination, calculation of dialysis adequacy and biochemical analysis and calculation of EHRI. Logarithmically converted EHRI (logEHRI) was correlated only with hemoglobin (r -0.381, P < 0.0001) and PLR (r = 0.227, P = 0.021) but not with NLR. Comparison of PLR among 25th, 50th and 75th percentile of EHRI showed that PLR levels increased going from the 25th to 75(th) percentile (P = 0.032). Posthoc analysis revealed that 25-75th percentile (P = 0.014) and 50-75th percentile (P = 0.033) were different with respect to PLR. In linear regression analysis, PLR (standardized β = 0.296, confidence interval: 0.000-0.001, P = 0.003) was independently associated with logEHRI. We found that PLR was independently associated with EHRI in HD patients. PLR, which is quite a simple and cheap method, may guide clinicians for detecting EPO resistance.

Topics: Aged; Anemia; Blood Platelets; Cross-Sectional Studies; Darbepoetin alfa; Drug Resistance; Erythropoietin; Female; Hematinics; Humans; Inflammation; Linear Models; Lymphocytes; Male; Middle Aged; Neutrophils; Predictive Value of Tests; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups.. Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none).. Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug.. This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS.. NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348.. F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Topics: Aged; Anemia; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Outcome and Process Assessment, Health Care; Polyethylene Glycols; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Statistics as Topic

Erythropoietin (EPO) may be a beneficial tissue-protective cytokine. However, high doses of EPO are associate with adverse effects, including thrombosis, tumor growth, and hypertension. Carbamylated erythropoietin (CEPO) lacks both erythropoietic and vasoconstrictive actions. In this study, we compared the renoprotective, hemodynamic, and hematologic activities and survival effects of identical EPO and CEPO doses in rat models of clinically relevant AKI presentations, including ischemia-reperfusion-induced AKI superimposed on CKD (5000 U/kg EPO or CEPO; three subcutaneous injections) and ischemia-reperfusion-induced AKI in old versus young animals and male versus female animals (1000 U/kg EPO or CEPO; three subcutaneous injections). Compared with EPO therapy, CEPO therapy induced greater improvements in renal function and body weight in AKI on CKD animals, with smaller increases in hematocrit levels and similarly improved survival. Compared with EPO therapy in the other AKI groups, CEPO therapy induced greater improvements in protection and recovery of renal function and survival, with smaller increases in systolic BP and hematocrit levels. Overall, old or male animals had more severe loss in kidney function and higher mortality rates than young or female animals, respectively. Notably, mRNA and protein expression analyses confirmed the renal expression of the heterodimeric EPO receptor/CD131 complex, which is required for the tissue-protective effects of CEPO signaling. In conclusion, CEPO improves renal function, body and kidney weight, and survival in AKI models without raising hematocrit levels and BP as substantially as EPO. Thus, CEPO therapy may be superior to EPO in improving outcomes in common forms of clinical AKI.

Topics: Acute Kidney Injury; Age Factors; Animals; Erythropoietin; Female; Male; Rats; Rats, Inbred F344; Renal Insufficiency, Chronic; Sex Factors

Anemia of chronic kidney disease (CKD) can be corrected by treatment with recombinant human erythropoietin (rHuEPO); however, some patients become hyporesponsive. The molecular mechanisms underlying this resistance remain to be elucidated. Our aim was to study hyporesponsiveness to rHuEPO therapy using the remnant kidney rat model of anemia associated with CKD induced by 5/6 nephrectomy. At starting, male Wistar rats were divided in 3 groups, for a 3-week protocol: Sham, CRF (vehicle) and two rHuEPO (200 k/kg body weight [BW]/week) treated groups; at the end of protocol, the rHuEPO treated rats were subdivided in responders (CRF200) and non-responders (CRF200NR), according to their hematologic response; blood, cellular and tissue studies were performed. The CRF200 group achieved correction of anemia, while the CRF200NR group developed anemia, after an initial response (1st week) to rHuEPO therapy. CRF and CRF200NR groups presented a trend to higher serum CRP levels; CRF200NR showed also high levels of renal inflammatory markers, such as interleukin (IL)-6, IL-1β, nuclear factor kappa B, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGF-β1); no changes were found in iron metabolism. Our data suggest that the development of anemia/rHuEPO hyporesponsiveness is associated with a higher systemic and renal inflammatory condition, favoring hypoxia and triggering an increase in renal expression of HIF-1α, TGF-β1 and CTGF that will further aggravate renal fibrosis, which will enhance the inflammatory response, creating a cycle that promotes disease progression. New therapeutic strategies to reduce inflammation in CKD patients could improve the response to rHuEPO therapy and reduce hyporesponsiveness.

Topics: Anemia; Animals; Cytokines; Disease Models, Animal; Drug Resistance; Erythropoietin; Humans; Male; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic

International clinical practice guidelines for the management of anemia in chronic kidney disease suggest target hemoglobin levels ≤ 11.5 g/dl (115 g/l), with individualized consideration of slightly higher hemoglobin targets to improve quality of life. An updated meta-analysis of randomized trials demonstrates no significant improvement in quality of life with erythropoietin-stimulating agent therapy targeting higher hemoglobin levels. Limitations of the available data suggest that individualized targets should nonetheless remain an option in future clinical practice guidelines.

Topics: Anemia; Erythropoietin; Hematinics; Hemoglobins; Humans; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are widely used for treating chronic kidney disease (CKD)-associated anemia. The biological activity of ESAs is mainly regulated by the number of sialic acid-containing carbohydrates on the erythropoietin (EPO) peptide. Sialidase, a sialic acid-metabolizing enzyme that accumulates in CKD patients, is suspected of contributing to shortening the circulation half-life of ESAs. Epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), is an EPO integrated with methoxypolyethylene glycol (PEG). It has been suggested that C.E.R.A. may exert a favorable therapeutic effect, even under conditions of elevated sialidase; however, no detailed investigation of the pharmacological profile of C.E.R.A. in the presence of sialidase has been reported. In the present study, we injected C.E.R.A. or EPO pre-incubated with sialidase into rats, and assessed the hematopoietic effect by reticulocyte count. The hematopoietic effect of C.E.R.A., but not EPO, was preserved after sialidase treatment, despite the removal of sialic acid. Proliferation of EPO-dependent leukemia cells (AS-E2) was significantly increased by desialylated C.E.R.A. and EPO compared to non-treated C.E.R.A. or EPO. In conclusion, we show that C.E.R.A. exerts a favorable hematopoietic effect even under conditions of elevated sialidase. Our findings may contribute to a better understanding of CKD and more effective therapeutic approaches based on a patient's profile of anemia.

Topics: Animals; Erythropoietin; Hematopoiesis; Neuraminidase; Polyethylene Glycols; Rats; Recombinant Proteins; Renal Insufficiency, Chronic; Reticulocyte Count; Sialic Acids

Reticulocyte hemoglobin content and percentage of hypochromic red cells are incorporated into the European best practice guidelines on anemia management in chronic kidney disease. Sysmex XN analyzer (Sysmex Corporation, Kobe, Japan) reports reticulocyte hemoglobin equivalent (Ret-He) and the hypochromic fraction of erythrocytes (%Hypo-He). Our aim was to assess the value of these parameters, in terms of the sensitivity and specificity for detecting functional iron deficiency, in hemodialysis (HD) patients.. Forty HD patients in the maintenance phase of erythropoietin therapy were included. Intravenous iron supplementation was interrupted at least 3 weeks before recruitment. Two samples were analyzed for each patient: the baseline after the iron-free period and the second sample after 4 weeks of IV iron administration. Hemogram and biochemical parameters of the iron status were measured. Patients were classified as responders or nonresponders to an iron load; responders had an increase in Hb of at least 10 g/L after iron administration, compared to the baseline. To identify the efficiency of the test for predicting the response to iron administration, receiver operating characteristic analysis (ROC) was performed.. According to the established criteria, 21 patients were responders and 19 nonresponders. ROC analysis results: Ret-He area under curve (AUC) was 0.84 (95% CI 0.64-0.93), at cutoff 30.8 pg, sensitivity 78.7%, and specificity 87.2%. % Hypo-He AUC was 0.78 (95% CI 0.64-0.91), at cutoff 2.4%, sensitivity 72.2%, and specificity 88.1%.. % Hypo-He and Ret-He are reliable parameters for the study of erythropoiesis status in HD patients.

Topics: Administration, Intravenous; Erythrocytes; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron; Middle Aged; Predictive Value of Tests; Renal Dialysis; Renal Insufficiency, Chronic; Reticulocytes; Sensitivity and Specificity

Functional iron deficiency (FID) is a major cause of persistent anemia in dialysis patients and also contributes to a suboptimal response to erythropoietin (Epo) administration. Vitamin C acts as an enzyme cofactor and enhances mobilization of the ferrous form of iron to transferrin thus increasing its bioavailability. High-dose intravenous vitamin C has been shown to decrease the Epo requirement and improve hemoglobin levels in previous studies. This study assessed the effect of low-dose oral vitamin C on possible reduction in Epo dose requirements in stable hemodialysis patients with FID.. This prospective study included 22 stable hemodialysis patients with FID defined as transferrin saturation (T sat) <30 % and ferritin levels of >100 mcg/L with Epo requirement of ≥4000 U/HD session. Patients received oral vitamin C 250 mg daily for 3 months. Hemoglobin, iron and T sat levels were recorded monthly. No one received iron supplementation during the study period.. There was a significant reduction in median Epo dose requirement in the 15 patients who completed the study, from 203.1 U/kg/week (95 % CI 188.4-270.6) to 172.8 U/kg/week (95 % CI 160.2-214.8), (P = 0.01). In the seven responders, there was 33 % reduction in Epo dose from their baseline. Despite adjustment of Epo dose, the mean hemoglobin level was significantly increased from 10.1 ± 0.6 to 10.7 ± 0.6 mg/dL (P = 0.03). No adverse effects of oral vitamin C were observed.. Daily low-dose oral vitamin C supplementation reduced Epo dose requirements in hemodialysis patients with FID. Limitations of this study include a small sample size and the lack of measurements of vitamin C and oxalate levels. Despite concerns regarding oral vitamin C absorption in dialysis patients, this study indicates vitamin C was well tolerated by all participants without reported adverse effect.

Topics: Administration, Oral; Adult; Aged; Ascorbic Acid; Dietary Supplements; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Deficiencies; Male; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Transferrin; Vitamins

Topics: Anemia, Iron-Deficiency; Erythropoietin; Hematinics; Humans; Iron; Iron Deficiencies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

To investigate the impact of anemia correction with erythropoiesis stimulants on the serum level of the circulating morphogenetic protein α-Klotho in patients with Stages 3B--4 chronic kidney disease (CKD).. 64 patients aged 42±8 years with Stages 3B--4 nondiabetic CKD were examined and divided into 2 groups: 1) 32 patients with anemia (the target hemoglobin levels could be achieved and kept with erythropoietin and iron saccharate in 20 patients (Group A) and those could not be done in 12 patients (Group 1B). A control group (Group 2) consisted of 32 non-anemic patients matched for gender, age, and degree of a glomerular filtration rate (GFR) reduction. Along with iron exchange indicators, the time course of changes in serum Klotho levels were examined in all the 64 patients during screening and one year after the end of the study. For correction of anemia, 32 patients with this condition (Groups 1A and 1B) took short-acting epoetin (hypodermic recormon 2,000 IU thrice per week + iron (intravenous venofer 5 ml of 100 mg once per week)) under control of hemoglobin levels and serum transferrin iron and ferritin saturation. After achieving the target hemoglobin level of 110-120 g/l, for its keeping, all the patients received, instead of short-acting epoetin, long-acting hypodermic darbepoetin-α 1.5 µg once every 2 months and intravenous iron saccharate 100 mg once every 2 weeks.. Among the 32 anemic patients in Group 1, 20 (63%) (Group 1 A) could achieve the target hemoglobin level (110--120 g/l) and maintain it within this range, by performing therapy with epoitin-β + iron saccharate; anemia (the hemoglobin level of <110 g/l) persisted in 12 (37%) patients (Group 1B) despite the fact that epoetin and iron saccharate had been administered. Group 1A was noted to have an increase in α-Klotho concentrations by an average of 100±11.6-pg/ml as compared to Group 1B (by only 72±4.2 pg/ml). At the same time, the α-Klotho levels in the control group by the end of the follow-up decreased by an average of 210±12.9 pg/ml as compared to the prescreening value. There was a direct correlation between hemoglobin and serum ferritin concentrations and iron ferritin saturation percentage and α-Klotho levels. It was ascertained that the hemoglobin concentration of ≥110 g/l with a sensitivity of 89% and a specificity of 75% could predict higher serum α-Klotho levels in CKD. The same patients were found to have an inverse relationship between the serum level of α-Klotho and the risk of cardiovascular events.. The serum level of the protein Klotho is not only a marker for the severity of CKD and its complications (anemia, left ventricular hypertrophy, and heart failure), but also a pathogenetic factor of CKD progression. Anemia correction with erythropoiesis stimulants has been shown to enhance the renal and extrarenal production of α-Klotho.. Цель исследования. Изучить влияние коррекции анемии препаратами, стимулирующими эритропоэз, на уровень в сыворотке крови циркулирующей формы морфогенетического белка α-Klotho у больных хронической болезнью почек (ХБП) 3Б-4 стадии. Материалы и методы. Обследовали 64 больных ХБП недиабетической этиологии 3Б-4 стадии в возрасте 42±8 лет, которых распределили в 2 группы: 1-я - 32 больных с анемией (у 20 с помощью эритропоэтина и железа сахарата удалось достичь и поддерживать целевой уровень гемоглобина - группа 1А, и 12, которым назначенная терапия не позволила достигнуть целевого уровня гемоглобина - группа 1Б). Группу контроля (2-я) составили 32 больных без анемии, сопоставимых с больными 1-й группы по полу, возрасту и степени снижения скорости клубочковой фильтрации (СКФ). У всех 64 больных во время скрининга и через 1 год после окончания исследования наряду с показателями обмена железа изучена динамика уровня Klotho в сыворотке. Для коррекции анемии 32 пациента с анемией (группы 1А и 1Б) получали эпоэтин короткого действия (рекормон по 2000 ЕД 3 раза в неделю подкожно) + железо (венофер 5 мл 100 мг 1 раз в неделю внутривенно) под контролем уровня гемоглобина, насыщения трансферрина железом и ферритина сыворотки. После достижения целевого уровня гемоглобина 110-120 г/л для его поддержания всем пациентам вместо эпоэтина короткого действия вводили эпоэтин длительного действия дабепоэтин-α 1,5 мкг на 1 кг 1 раз в 2 мес подкожно и железа сахарат 100 мг 1 раз в 2 нед внутривенно. Результаты. Среди 32 больных 1-й группы с анемией у 20 (63%) (группа 1А) терапия эпоэтином-β + железа сахаратом позволила достигнуть целевого уровня гемоглобина (110-120 г/л) и поддерживать его в этом диапазоне; у 12 (37%) больных (группа 1Б), несмотря на введение эпоэтина и железа сахарата, сохранялась анемия (уровень гемоглобина <110 г/л). У больных группы 1А отмечено увеличение концентрации α-Klotho в среднем на 100±11,6 пг/мл по сравнению с таковой у больных группы 1Б (только на 72±4,2 пг/мл). В то же время в контрольной группе к концу наблюдения уровень α-Klotho уменьшился в среднем на 210±12,9 пг/мл по сравнению с таковой до скрининга. Отмечена прямая связь между концентрацией гемоглобина, ферритина в сыворотке крови и процентом насыщения железом трансферрина и уровнем α-Klotho. Выявлено, что концентрация гемоглобина ≥110 г/л с чувствительностью 89% и специфичностью 75% позволяет прогнозировать выявление более высокого уровня α-Klotho в сыворотке крови при ХБП. У тех же больных о

Topics: Adult; Anemia; Biomarkers; Disease Progression; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Glucuronidase; Hematinics; Hemoglobins; Humans; Iron; Klotho Proteins; Male; Middle Aged; Outcome Assessment, Health Care; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index

In many elderly patients with anemia, a specific cause cannot be identified. This study investigates whether erythropoietin levels are inappropriately low in these cases of "anemia of unknown etiology" and whether this trend persists after accounting for confounders.. This study includes all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient's anemia to one of ten etiologies: chronic kidney disease, iron deficiency, chronic disease, confirmed myelodysplastic syndrome (MDS), suspected MDS, vitamin B12 deficiency, folate deficiency, anemia of unknown etiology, other etiology, or multifactorial etiology. Iron deficiency anemia served as the comparison group in all analyses. We used linear regression to model the relationship between erythropoietin and the presence of each etiology, sequentially adding terms to the model to account for the hemoglobin concentration, estimated glomerular filtration rate (eGFR) and Charlson Comorbidity Index.. A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic disease and anemia of unknown etiology were lower by 48%, 46% and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin, eGFR and comorbidities.. We have shown that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This suggests that decreased erythropoietin production may play a key role in the pathogenesis of anemia of unknown etiology.

Topics: Aged; Aged, 80 and over; Anemia; Anemia, Iron-Deficiency; Biomarkers; Chronic Disease; Comorbidity; Erythropoietin; Female; Folic Acid Deficiency; Glomerular Filtration Rate; Hematologic Tests; Hemoglobins; Humans; Linear Models; Male; Middle Aged; Myelodysplastic Syndromes; Renal Insufficiency, Chronic; Retrospective Studies; Vitamin B 12 Deficiency

Mechanisms of accelerated atherothrombosis in patients with chronic kidney disease (CKD) are only partly characterized. The aims of this study were to evaluate the extent of thromboxane (TX)-dependent platelet activation in patients with CKD, and to characterize the determinants of altered TX biosynthesis in this setting, with particular reference to enhanced lipid peroxidation, low grade inflammation and CKD-related anemia.. A cross sectional comparison between urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, was performed in 115 patients with stage 1-4 CKD.. Levels of both urinary 11-dehydro-TXB2 and 8-iso-PGF2α increased sequentially across the four CKD stages (P<0.0001, Kruskal-Wallis test). Both urinary prostanoids were inversely associated with either estimated glomerular filtration rate (eGFR, P<0.0001) or hemoglobin levels (P<0.0001). A significant direct correlation was also observed between urinary 11-dehydro-TXB2 and 8-iso-PGF2α (Rho=0.620, P<0.0001). On multivariate analysis, urinary 8-iso-PGF2α (β=0.459, P<0.0001), hemoglobin levels (β=- 0.261, P=0.002) and eGFR (β=-0.172, P=0.032) were independent predictors of urinary 11-dehydro-TXB2 (adjusted R(2)=0.488).. This study provides biochemical evidence of persistent platelet activation in patients with CKD. This condition occurs early in the natural history of the disease and is related to kidney function and oxidative stress. Moreover, we found an independent inverse relationship between hemoglobin levels and TX-dependent platelet activation. This finding may provide a mechanistic link between CKD-related anemia and increased cardiovascular risk.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Dinoprost; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Italy; Linear Models; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Platelet Activation; Prostaglandins; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Thromboxane B2

Chronic kidney disease (CKD) is known to increase myocardial infarct size after ischemia/reperfusion. However, a strategy to prevent the CKD-induced myocardial susceptibility to ischemia/reperfusion injury has not been developed. Here, we examined whether epoetin β pegol, a continuous erythropoietin receptor activator (CERA), normalizes myocardial susceptibility to ischemia/reperfusion injury by its effects on protective signaling and metabolomes in CKD. CKD was induced by 5/6 nephrectomy in rats (subtotal nephrectomy, SNx), whereas sham-operated rats served controls (Sham). Infarct size as percentage of area at risk after 20-minutes coronary occlusion/2-hour reperfusion was larger in SNx than in Sham: 60.0±4.0% versus 43.9±2.2%. Administration of CERA (0.6 μg/kg SC every 7 days) for 4 weeks reduced infarct size in SNx (infarct size as percentage of area at risk=36.9±3.9%), although a protective effect was not detected for the acute injection of CERA. Immunoblot analyses revealed that myocardial phospho-Akt-Ser473 levels under baseline conditions and on reperfusion were lower in SNx than in Sham, and CERA restored the Akt phosphorylation on reperfusion. Metabolomic analyses showed that glucose 6-phosphate and glucose 1-phosphate were reduced and malate:aspartate ratio was 1.6-fold higher in SNx than in Sham, suggesting disturbed flux of malate-aspartate shuttle by CKD. The CERA improved the malate:aspartate ratio in SNx to the control level. In H9c2 cells, mitochondrial Akt phosphorylation by insulin-like growth factor-1 was attenuated by malate-aspartate shuttle inhibition. In conclusion, the results suggest that a CERA prevents CKD-induced susceptibility of the myocardium to ischemia/reperfusion injury by restoration of Akt-mediated signaling possibly via normalized malate-aspartate shuttle flux.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Drug Administration Schedule; Erythropoietin; Injections, Subcutaneous; Male; Metabolome; Myocardial Infarction; Myocardial Reperfusion Injury; Nephrectomy; Phosphorylation; Polyethylene Glycols; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Reference Values; Renal Insufficiency, Chronic; Sensitivity and Specificity

Chronic kidney disease (CKD) is often accompanied by impairment of cardiac function that may lead to major cardiac events. Erythropoietin (EPO), a kidney-produced protein, was shown to be beneficial to heart function. It was suggested that reduced EPO secretion in CKD may play a role in the initiation of heart damage.. To investigate molecular changes in the EPO/ erythropoietin receptor (EPO-R) axis in rat cardiomyocytes using a rat model for CKD.. We established a rat model for CKD by kidney resection. Cardiac tissue sections were stained with Masson's trichrome to assess interstitial fibrosis indicating cardiac damage. To evaluate changes in the EPO/EPO-R signaling cascade in the myocardium we measured cardiac EPO and EPO-R as well as the phosphorylation levels of STAT-5, a downstream element in this cascade.. At 11 weeks after resection, animals presented severe renal failure reflected by reduced creatinine clearance, elevated blood urea nitrogen and presence of anemia. Histological analysis revealed enhanced fibrosis in cardiac sections of CKD animals compared to the sham controls. Parallel to these changes, we found that although cardiac EPO levels were similar in both groups, the expression of EPO-R and the activated form of its downstream protein STAT-5 were significantly lower in CKD animals.. CKD results in molecular changes in the EPO/EPO-R axis. These changes may play a role in early cardiac damage observed in the cardiorenal syndrome.

Topics: Anemia; Animals; Disease Models, Animal; Down-Regulation; Erythropoietin; Fibrosis; Kidney Function Tests; Male; Myocardium; Rats; Receptors, Erythropoietin; Renal Insufficiency, Chronic; Signal Transduction; STAT5 Transcription Factor

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Renal Insufficiency, Chronic

Vitamin D (25-hydroxyvitamin D; 25[OH]D) deficiency (VDD) is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effect of oral ergocalciferol supplementation on requirement of erythropoietin (EPO) and active vitamin D analogues, and hospitalization rate in maintenance hemodialysis (HD) patients.. This retrospective cohort study included 186 patients who were on HD for 3 months and had 25(OH)D levels < 30 ng/ml. Over 1-year period, 107 patients were supplemented with protocol-based ergocalciferol (D. One-year of ergocalciferol supplementation was not associated with reduction in EPO requirement or hospitalization rate in HD patients with VDD. Further studies are warranted to determine definitive role of nutritional vitamin D in these patients.

Topics: Administration, Oral; Adult; Aged; Cohort Studies; Ergocalciferols; Erythropoietin; Female; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome; Vitamin D; Vitamins

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

Topics: Aged; Cohort Studies; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Survival Rate; Treatment Outcome

Erythropoietin (EPO) is used to treat anaemia associated with chronic kidney disease (CKD). Hypoxia is associated with anaemia and is known to cause a decrease in cytochrome P450 (P450) expression. As EPO production is regulated by hypoxia, we investigated the role of EPO on P450 expression and function.. Male Wistar rats were subjected to a 0.7% adenine diet for 4 weeks to induce CKD. The diet continued for an additional 2 weeks while rats received EPO by i.p. injection every other day. Following euthanasia, hepatic P450 mRNA and protein expression were determined. Hepatic enzyme activity of selected P450s was determined and chromatin immunoprecipitation was used to characterize binding of nuclear receptors involved in the transcriptional regulation of CYP2C and CYP3A.. EPO administration decreased hepatic mRNA and protein expression of CYP3A2 (P < 0.05), but not CYP2C11. Similarly, EPO administration decreased CYP3A2 protein expression by 81% (P < 0.001). A 32% decrease (P < 0.05) in hepatic CYP3A enzymatic activity (Vmax ) was observed for the formation of 6βOH-testosterone in the EPO-treated group. Decreases in RNA pol II recruitment (P < 0.01), hepatocyte nuclear factor 4α binding (P < 0.05) and pregnane X receptor binding (P < 0.01) to the promoter region of CYP3A were also observed in EPO-treated rats.. Our data show that EPO decreases the expression and function of CYP3A, but not CYP2C in rat liver.

Topics: Adenine; Animals; Constitutive Androstane Receptor; Cytochrome P-450 Enzyme System; Diet; Disease Models, Animal; Erythropoietin; Hepatocyte Nuclear Factor 4; Kidney; Liver; Male; Microsomes, Liver; Pregnane X Receptor; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Recombinant Proteins; Renal Insufficiency, Chronic; RNA Polymerase II; RNA, Messenger

C.E.R.A. (continuous erythropoietin receptor activator, pegilated-rHuEPO ß) corrects and maintains stable hemoglobin levels in once-monthly administration in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the management of anemia with C.E.R.A. in CKD patients not on dialysis in the clinical setting.. Two hundred seventy two anemic CKD patients not on dialysis treated with C.E.R.A. were included in this retrospective, observational, multicentric study during 2010. Demographical characteristics, analytical parameters concerning anemia, treatment data and iron status were recorded.. C.E.R.A. achieved a good control of anemia in both naïve patients (mean Hemoglobin 11.6g/dL) and patients converted from a previous ESA (mean Hemoglobin 11.7g/dL). Most naïve patients received C.E.R.A. once monthly during the correction phase and required a low monthly dose (median dose 75 µg/month). The same median dose was required in patients converted from a previous ESA, and it was lower than recommended in the Summary of Product Characteristics (SPC). Iron status was adequate in 75% of anemic CKD patients, but only 50% of anemic patients with iron deficiency received iron supplementation.. C.E.R.A. corrects and maintains stable hemoglobin levels in anemic CKD patients not on dialysis, requiring conversion doses lower than those recommended by the SPC, and achieving target hemoglobin levels with once-monthly dosing frequency both in naïve and converted patients.

Topics: Adolescent; Adult; Aged; Anemia; Anemia, Iron-Deficiency; Diabetic Nephropathies; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Iron; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Retrospective Studies; Young Adult

Biologic drugs, including epoetin, continue to play an important role in the management of medical conditions. However, biologics are costly and soon many of the patents on these drugs will expire, making way for non-brand name products (ie, biosimilars). It is only by introducing competition to the marketplace that costs will de-escalate. In Europe, a specific regulatory pathway for approving biosimilars has been in place since 2005. A similar review pathway in the United States has been developed by the US Food and Drug Administration. These guidelines for approving biosimilars are stringent, requiring preclinical pharmacodynamic and toxicologic studies, clinical studies to demonstrate bioequivalence and efficacy, and long-term postmarketing studies to monitor drug safety. Biosimilar epoetin has been used in Europe since 2007, and a wealth of data has been collected. These studies and reports indicate that the efficacy and safety profiles of biosimilar epoetin are similar to those of originator epoetin alfa. Biosimilars of epoetin alfa are expected to be among the first biosimilar agents to be approved for use in the United States. The availability of lower cost epoetins may have significant impact on the treatment of anemia of chronic kidney disease.

Topics: Anemia; Biosimilar Pharmaceuticals; Drug Approval; Epoetin Alfa; Erythropoietin; Health Care Costs; Hematinics; Humans; Nephrology; Recombinant Proteins; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration

Comparative studies of the potency of long- and short-acting erythropoiesis-stimulating agents (L-ESAs and S-ESAs) on erythropoietic activity in patients with chronic kidney disease without dialysis have not been performed, although L-ESAs are used in many countries. We performed a retrospective analysis of non-dialysis (ND) patients who had received L-ESA or S-ESA. More days were needed for the S-ESA-treated group (368 d) to reach the haemoglobin (Hb) reference range than for the L-ESA-treated group (126 d). Therefore, we investigated risk factors that influence the period until the Hb level reaches the reference range. Patients were classified into two groups by the period until the Hb level was stabilised within the reference range: the short- and long-term group. Two risk factors for delayed Hb stabilisation were identified: age ≥60 years; and administration of an S-ESA for initial treatment. These findings suggest that the Hb level should be carefully monitored during ESA therapy in elderly ND patients, and that the ESA dose should be increased or L-ESA therapy should be utilised to treat renal anaemia.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors

Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking.. Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO.. Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure.. DPO versus EPO.. All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.. Unadjusted and adjusted HRs from Cox proportional hazards regression models.. Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25).. Nonrandom treatment assignment, potential residual confounding.. In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO.

Topics: Aged; Ambulatory Care Facilities; Anemia; Cardiovascular Diseases; Cause of Death; Comorbidity; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemodialysis Units, Hospital; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Recombinant Proteins; Registries; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Stroke; Treatment Outcome; United States

Mesenchymal stem cells (MSCs) play a central role in the remediation of cell and tissue damage. Erythropoietin (EPO) may enhance the beneficial influence of MSCs during recovery from tissue and organ injuries. Microvesicles (MVs) released from MSCs contribute to the restoration of kidney damage. We studied the influence of EPO on MVs derived from MSCs, and the protective effects of these factors in subjects with chronic kidney disease (CKD).. The MVs derived from untreated MSCs (MSC-MVs) or from MSCs incubated in different concentrations of EPO (1, 10, 100, and 500 IU/ml EPO-MVs) were used to treat renal injury of unilateral ureteral obstruction (UUO) in vivo, and transforming growth factor-β1 (TGF-β1)-induced fibrosis in a human renal proximal tubular epithelial (HK2) cell line in vitro. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses were used to evaluate the expression of epithelial and mesenchymal markers in the renal tissue and HK2 cells. Flow cytometry was used to assess apoptosis within the HK2 cells, and microRNA (miRNA) microarray assays were used to determine the expression profiles of miRNA in the MSC-MVs and EPO-MVs.. Compared to MSC-MVs (untreated), there was a significant increase in the number of EPO-MVs derived from MSCs treated with 1-100 IU/ml EPO, and these EPO-MVs had a greater benefit in UUO mice on days 7 and 14. Moreover, the EPO-MVs had a better restorative effect following TGF-β1-induced fibrosis in HK2 cells at 24 h and 48 h. The flow cytometry results revealed that both types of MVs, especially EPO-MVs, play an important anti-apoptotic role in HK2 cells treated with TGF-β1. The miRNA profiles of the MVs revealed that EPO-MVs changed 212 miRNAs (fold-change ≥ 1.5), including miR-299, miR-499, miR-302, and miRNA-200, and that 70.28 % of these changes involved upregulation. The changed miRNA in EPO-MVs may have contributed to their enhanced protective effects following renal injury compared to MSC-MVs.. There was a dose-dependent increase in the level of EPO-MVs within the range of 1-100 IU/ml EPO. Although both MSC-MVs and EPO-MVs protect the kidney from fibrosis-related damage, there is a superior effect of EPO-MVs.

Topics: Actins; Animals; Apoptosis; Bone Marrow Cells; Cadherins; Cell-Derived Microparticles; Cells, Cultured; Disease Models, Animal; Erythropoietin; Fibrosis; Humans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Transcriptome; Transforming Growth Factor beta1; Ureteral Obstruction

Erythropoietin, Epo, is a 30.4 kDa glycoprotein hormone produced primarily by the fetal liver and the adult kidney. Epo exerts its haematopoietic effects by stimulating the proliferation and differentiation of erythrocytes with subsequent improved tissue oxygenation. Epo receptors are furthermore expressed in non-haematopoietic tissue and today, Epo is recognised as a cytokine with many pleiotropic effects. We hypothesize that hydrodynamic gene therapy with Epo can restore haemoglobin levels in anaemic transgenic mice and that this will attenuate the extracellular matrix accumulation in the kidneys. The experiment is conducted by hydrodynamic gene transfer of a plasmid encoding murine Epo in a transgenic mouse model that overexpresses TGF-β1 locally in the kidneys. This model develops anaemia due to chronic kidney disease characterised by thickening of the glomerular basement membrane, deposition of mesangial matrix and mild interstitial fibrosis. A group of age matched wildtype littermates are treated accordingly. After a single hydrodynamic administration of plasmid DNA containing murine EPO gene, sustained high haemoglobin levels are observed in both transgenic and wildtype mice from 7.5 ± 0.6 mmol/L to 9.4 ± 1.2 mmol/L and 10.7 ± 0.3 mmol/L to 15.5 ± 0.5 mmol/L, respectively. We did not observe any effects in the thickness of glomerular or tubular basement membrane, on the expression of different collagen types in the kidneys or in kidney function after prolonged treatment with Epo. Thus, Epo treatment in this model of chronic kidney disease normalises haemoglobin levels but has no effect on kidney fibrosis or function.

Topics: Anemia; Animals; Collagen; Disease Models, Animal; Disease Progression; Erythropoietin; Fibronectins; Genetic Therapy; Glomerular Basement Membrane; Hemoglobins; Kidney; Liver; Male; Mice; Mice, Transgenic; Plasmids; Renal Insufficiency, Chronic; Transforming Growth Factor beta1

Topics: Adult; Aged; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Inflammation and increased erythropoiesis stimulating agents (ESA) requirement are frequently associated in patients on dialysis. On-line hemodiafiltration (ol-HDF), putting together high levels of diffusion, and convection could improve both conditions. However, it is still not known which depurative component plays a major role in determining this result. The aim of the study was to evaluate the role of convection and diffusion on long-term variations of serum β2 microglobulin (Δβ2M), high-sensitive C-reactive protein (ΔhsCRP) concentrations, and ESA requirement (ΔESA) in ol-HDF.. Seventy-three patients prevalent on high flux HD (hfHD) were studied. Thirty-eight patients were switched from hfHD to post-dilutional ol-HDF (Study group); the other 35 patients were considered the Control group. At 6 and 12 months, the effects of ol-HDF and hfHD on ΔhsCRP, ΔB2M, and ΔESA (U/kg/week) were evaluated. Other variables considered were body weight (BW), serum albumin (sAlb), hemoglobin (Hb), and equilibrated Kt/V (eKt/V). Iron therapy and ESA were administered intravenously according to the K/DOQI guidelines in order to maintain transferrin saturation between 20 and 40%, serum ferritin between 150 and 500 ng/ml and Hb between 11 and 12 g/dl. Qb, treatment time and Qd remained constant. Ol-HDF and hfHD were performed using membranes of size 1.9-2.1 sqm. Ultrapure dialysate and substitution fluid were employed in both HDF and HD treatments. Data are expressed as mean ± SD. Paired t test, Mann-Whitney U test, and simple and multiple regression analyses were employed for statistical evaluation.. total convective volume (TCV) was 22.1 ± 1.9 l/session. A significant reduction of hsCRP: from 6.8 ± 7.1 to 2.3 ± 2.4 mg/dl (p < 0.001), β2M: from 36.5 ± 14.4 to 24.7 ± 8.6 mg/dl (p < 0.0001) and ESAdose: from 107 ± 67 to 65 ± 44 U/kg/week (p < 0.005) was observed. No significant variations of Hb, BW and sAlb were seen. A significant inverse correlation was found between TCV and Δβ2M (r = -0.627; p < 0.0001), and TCV and ΔhsCRP (r = -0.514; p < 0.0001); no correlation between TCV and ΔESAdose was observed. No correlation was found between eKt/V and Δβ2M, ΔhsCRP, and ΔESAdose. Multiple regression analysis with ΔESAdose as dependent variable showed ΔhsCRP as the only significantly associated independent factor (p < 0.01).. no significant variations of hsCRP, β2M, and ESAdose were observed over time.. Ol-HDF induces a long-term significant reduction in pre-dialysis β2M and hsCRP concentrations. The magnitude of reduction is directly correlated to the amount of TCV achieved but not on eKt/V. The observed reduction in ESAdose requirement is independent either on convection or diffusion, but is directly associated to the concomitant reduction of inflammation.

Topics: Aged; beta 2-Microglobulin; Body Weight; C-Reactive Protein; Convection; Diffusion; Erythropoietin; Female; Ferritins; Hematinics; Hemodiafiltration; Hemoglobins; Humans; Iron; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Serum Albumin; Time Factors; Transferrin

In chronic kidney disease (CKD), anemia and hypertension are significant co-morbidities that contribute to cardiovascular and renal disease progression.. The purpose of the study was to identify correlations between changes in hematologic variables against markers of renal function, blood pressure, and erythropoietin (EPO) in a naturally occurring hypertensive model of CKD, the Lewis polycystic kidney (LPK) rat.. Complete blood count, systolic blood pressure, urea and creatinine concentration, urinary protein to creatinine ratio, and plasma EPO concentration were determined in control Lewis (n = 51) and LPK rats (n = 56) aged 6-24 weeks. Renal EPO gene expression and RBC osmotic fragility were also documented. Hematopoiesis in spleen and bone marrow were assessed.. Lewis polycystic kidney rats had increasing urea and creatinine concentrations, concurrent with the development of a nonregenerative normocytic/normochromic anemia and hypertension, with a significant negative correlation between both HGB and HCT with urea concentration and blood pressure (P < .01). HCT was also significantly negatively correlated with creatinine concentration (P = .014). WBC was significantly negatively correlated with urea (P < .01). Plasma EPO concentration was increased and renal EPO mRNA expression was significantly upregulated in LPK animals. The former was significantly positively correlated with blood pressure and platelet count (P < .05). RBC osmotic fragility was normal in LPK rats and there was no evidence for increased RBC elimination or extramedullary hematopoiesis.. Marked anemia in the LPK CKD rodent model in the presence of elevated EPO suggests inefficient erythropoiesis that is correlated with plasma urea concentration and blood pressure.

Topics: Anemia; Animals; Blood Cell Count; Blood Pressure; Blood Urea Nitrogen; Cohort Studies; Creatinine; Disease Models, Animal; Disease Progression; Erythropoietin; Female; Hypertension; Kidney; Kidney Function Tests; Male; Polycystic Kidney Diseases; Rats; Rats, Inbred Lew; Renal Insufficiency, Chronic

Hemodialysis (HD) patients occasionally experience minor asymptomatic elevation in C-reactive protein (CRP) levels, which may be associated with difficulty in managing renal anemia using erythropoiesis-stimulating agents (ESAs). Here, we assessed whether elevation of CRP predicts future incidences of ESA hyporesponsiveness.. A total of 2,956 HD patients lacking ESA hyporesponsiveness and infectious diseases were enrolled, and the association between CRP levels and incidence of ESA hyporesponsiveness was assessed. CRP levels were divided into 4 categories (normal [<1.0 mg/l], mild [1.0 ≤ CRP <3.0 mg/l], moderate [3.0 ≤ CRP <10.0 mg/l] and high [≥ 10.0 mg/l]). The primary outcome was the cumulative incidence of ESA hyporesponsiveness, defined as a failure to achieve hemoglobin level ≥ 10 g/dl despite receiving high doses of ESAs (≥ 9,000 U/week recombinant human epoetin [rHuEPO]-α or rHuEPO-β and ≥ 60 μg/week darbepoetin-α) during 12 months of follow-up.. The cumulative incidence of ESA hyporesponsiveness was 134 (4.8%) occurrences over 4 months and 300 (12.4%) over 12 months. The elevated CRP groups had significantly higher incidence of ESA hyporesponsiveness over 4 months of follow-up than the normal reference group (adjusted relative risk [RR] 1.6, 95% CI 1.0-2.6 for moderate; adjusted RR 2.5, 95% CI 1.5-4.1 for high). Furthermore, the association remained consistent even over 12 months (adjusted RR 1.4, 95% CI 1.0-1.8 for moderate; adjusted RR 1.6, 95% CI 1.1-2.4 for high).. Elevated CRP levels were associated with future incidence of ESA hyporesponsiveness from low-grade inflammation (3.0 ≤ CRP <10.0 mg/l).

Topics: Adult; Aged; Anemia; C-Reactive Protein; Drug Resistance; Erythropoiesis; Erythropoietin; Female; Hematinics; Humans; Japan; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Some data in literature indicate increased apoptosis of polymorphonuclear cells (PMNs) in chronic kidney disease (CKD), what seems to be connected with anemia. Erythropoiesis-stimulating agents, used in anemia treatment in CKD may affect cells apoptosis. Aim of this study was to investigate impact of anemia treatment with methoxy polyethylene glycol-epoetin beta (CERA) on PMNs apoptosis in predialysis patients with CKD.. Percentage of early and late apoptotic PMNs was measured by flow cytometry based on annexin V and propidium iodide binding. CD90 (Fas), CD95L (FasL), CD16 and CD11b expression on PMNs were evaluated by flow cytometry after incubation with respective monoclonal antibody.. Percentage of PMNs in early and late apoptosis in CKD patients before CERA treatment was significantly higher to control group, which was accompanied by significantly higher Fas and Fas-L expression and significantly lower expression of CD16. CERA treatment downregulated significantly percentage of early, apoptotic PMNs but percentage of late apoptotic cells did not change and was still significantly higher to control group. In all investigated groups we observed a significant negative correlation between hemoglobin concentration and percentage of apoptotic PMNs, as well as Fas and FasL expression and significant positive correlation between Hb and CD16 expression.. Our results indicate that PMNs apoptosis is increased in predialysis patients with CKD and anemia treatment with CERA may diminish readiness of PMNs to undergo apoptosis. This antiapoptotic impact of anemia treatment with CERA seems to concern early apoptotic PMNs before they undergo to late, irreversible stage of apoptosis.

Topics: Adult; Anemia; Apoptosis; Erythropoietin; Female; Flow Cytometry; Humans; Male; Neutrophils; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) patients have a poor prognosis due to cardiovascular disease. Anemia and endothelial dysfunction are important risk factors for cardiovascular events in CKD patients, and treatment with erythropoiesis-stimulating agent (ESA) has been reported to improve the quality of life in CKD patients. In this study, we evaluated the effect of anemia correcting dose of epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) on endothelial function in 5/6 nephrectomized rats (Nx rats). C.E.R.A. was subcutaneously administered once a fortnight, 5 times in total, from 1 week after nephrectomy. Twenty-four hours after last administration, endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anesthetized Nx rats by ultrasound system. Femoral arteries were harvested for western blot analysis. C.E.R.A. significantly increased FMD of Nx rats. Endothelium-independent vasodilation induced by nitroglycerin injection was not influenced by C.E.R.A treatment. Nox4 expression and nitrotyrosine accumulation were significantly decreased, and phosphorylation of eNOS was significantly enhanced in the femoral arteries of C.E.R.A.-treated rats. C.E.R.A. normalized hemoglobin levels but did not affect body weight, systolic blood pressure, heart rate, urinary protein excretion and plasma creatinine. These results indicate that C.E.R.A. prevented endothelial dysfunction in Nx rats, possibly through reduction of local oxidative stress and enhancement of eNOS phosphorylation in the arteries. This study provides the first evidence that C.E.R.A. prevented endothelial dysfunction in CKD model rats under conditions of amelioration of anemia.

Topics: Animals; Blood Pressure; Body Weight; Creatinine; Disease Models, Animal; Endothelium, Vascular; Erythropoietin; Femoral Artery; Heart Rate; Hemoglobins; Kidney Function Tests; Male; NADPH Oxidase 4; NADPH Oxidases; Nephrectomy; Nitric Oxide Synthase Type III; Nitroglycerin; Polyethylene Glycols; Proteinuria; Rats; Renal Insufficiency, Chronic; Tyrosine; Ultrasonography; Vasodilation

Erythropoiesis-stimulating agent (ESA) treatment during the predialysis period can be a strategy to reduce cardiac mortality soon after initiation of dialysis. In this study, we compared the efficacy of continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) in patients with chronic kidney disease (CKD) over 6 months prior to initiation of dialysis.. This study was a retrospective propensity score-matched study conducted at a single center in Japan that analyzed the effects of CERA and DA therapy on haemoglobin (Hb) changes, ESA resistance index (ERI) changes, and interval of ESA administration during a 6-month observation period prior to initiation of dialysis. Propensity scores were used for matching the patients included in the CERA and DA groups.. Among 680 screened, 74 pairs of patients (one in each group) were included in the present analysis after propensity score matching. Mean Hb significantly decreased over 6 months in the DA group compared to that in the CERA group (-0.70 ± 0.23 vs. -0.33 ± 0.22). In the DA group, mean ERI was significantly increased at 4, 3, 2, and 1 month before dialysis and initiation of dialysis, while in the CERA group, mean ERI was significantly increased only at 1 month before dialysis and initiation of dialysis. Moreover, patients administered CERA were required to visit the hospital significantly less frequently for ESA administration than those administered DA.. Our study showed that CERA may be more effective than DA for management of anaemia during the predialysis period in CKD patients.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Japan; Male; Polyethylene Glycols; Propensity Score; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

Erythropoiesis-stimulating agents (ESAs) are all effective for renal anaemia in patients with chronic kidney disease (CKD). However, it was reported that the haemoglobin (Hb) concentration decreases to 8.4 g/dL during the initial phase of dialysis despite treatment with recombinant human erythropoietin (rHuEPO). This study compared Hb at the initiation of dialysis among patients treated with three different ESAs (rHuEPO, darbepoetin alfa [DA], and a continuous erythropoietin receptor activator [CERA]).. The subjects were 82 CKD patients who started dialysis at Kawashima Hospital between 1 January 2009 and 28 February 2015 and who received only one kind of ESA for at least 6 months before initiation of dialysis. Baseline characteristics and laboratory data at initiation of dialysis were compared among the three groups. Then changes of the Hb, ESA dose, and erythropoiesis resistance index were assessed over time during the 6 months before initiation of dialysis. Differences of Hb at the initiation of dialysis were also assessed.. Among the 82 patients, 36 received rHuEPO, 13 received DA, and 33 received CERA. Baseline characteristics and laboratory data of the patients showed no significant differences among the three groups. The monthly Hb decreased gradually during the 6-month period before initiation of dialysis in all three groups. Hb was significantly higher in the CERA group than the rHuEPO group at the initiation of dialysis.. Long-acting ESAs may be more useful for predialysis patients with CKD because they do not attend hospital frequently, unlike haemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Iron; Iron Deficiencies; Practice Guidelines as Topic; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) is highly prevalent in the elderly and negatively impacts survival and health status. Thus, nephrological competence is mandatory for a skilled geriatrician. The present study aimed to assess nephrological competence in a sample of geriatricians recruited through a web survey. To this aim, a 12-items questionnaire was produced by an expert panel of nephrologists and geriatricians and was available online for members of the Italian Society of Gerontology and Geriatrics (SIGG). Two-hundred-eighty-seven geriatricians volunteered to fill in the questionnaire. The majority of them indirectly estimated the glomerular filtration rate (GFR) using mainly the Cockroft-Gault (C-G) formula. Selected nephrological exams, such as urinary Na and serum D-vitamin measurements, did not qualify as routine exams although the majority of geriatricians supplemented their patients with fat-soluble secosteroids. Ten percent of geriatricians asked for nephrological consultation only for stage 5 CKD patients and 30,9% only for stage 4 or 5. Erythropoietin supplementation was common practice for the majority of geriatricians, while only one third of them systematically used a procedure intended to prevent the contrast induced nephropathy (CIN). Finally, an alleged 50% adherence to the international guidelines for the management of CKD patients emerged from the questionnaire. Overall, results from this survey strongly recommend promoting nephrological education among geriatricians. Didactic standards for in training geriatricians need to be updated and the cooperation between geriatrics and nephrological societies promoted.

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Geriatric Assessment; Humans; Internet; Male; Medication Adherence; Renal Insufficiency, Chronic; Sodium; Surveys and Questionnaires; Vitamin D

Topics: Erythropoietin; Hematinics; Humans; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients.. This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated.. No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA.. It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Humans; Hypertension; Male; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies

This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.

Topics: Anemia; Animals; Antibodies; Drug Resistance; Duodenum; Erythropoietin; Humans; Iron; Kidney; Liver; Male; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic

In children with chronic kidney disease (CKD) anemia and calcium-phosphate disturbances are already present at early stages of the disease and require a comprehensive treatment. The aim of this study was to evaluate the efficacy of the treatment of biochemical disturbances, depending on the severity of CKD in children.. The study included 71 children (44 boys, 27 girls) with CKD stage 1-5. Mean age was 11 ± 5 years, mean height: 135.7 ± 28 cm and mean eGFR 32 ml/min/1.73 m2. The serum hemoglobin, urea, creatinine, cystatin C, calcium, phosphorus and parathyroid hormone (PTH) levels were measured. eGFR was calculated according to Schwartz and Filler formulas, employing creatinine and cystatin C as markers. Patients were divided into groups depending on the stage of CKD [group 1: CKD stage 1+2 (GFR > 60), group 2: CKD stage 3 (GFR = 30-59) Group 3: CKD stage 4 (GFR = 15-29 ml/min/1.73 m2), group 4 - dialyzed children].. The concentration of he- moglobin depending on the stage of CKD (group 1 vs. group 2 vs. group 3 vs group 4) was 12.95 vs. 12.68 vs. 12.47 vs. 11.3 g/dI, respectively. The concentration of total and ionized calcium was significantly lower in children on dialysis compared to patients treated conservatively. With the progression of CKD the concentration of phosphorus (1.39 vs. 1.4 vs. 1.49 vs. 1.82 mmolI) and PTH (21.7 vs 48.6 vs 99.9 vs. 219 pg/ml) significantly increased. Treatment with erythropoietin was used in 48% of children, calcium carbonate in 55% and alphacalcidol in 56% of patients.. Despite the use of regular treatment, with the progression of CKD a progression of anemia, increased serum phosphate and parathyroid hormone and a decrease in calcium levels in studied children was observed. The severity of metabolic disorders in dialyzed children indicates the need for administration of new and more effective drugs, to prevent early enough complications of CKD in the form of mineral bone disease and cardiovascular complications.

Topics: Adolescent; Anemia; Calcium Carbonate; Child; Disease Progression; Erythropoietin; Female; Humans; Hydroxycholecalciferols; Hyperphosphatemia; Hypocalcemia; Male; Parathyroid Hormone; Renal Insufficiency, Chronic; Treatment Outcome

Topics: Bipolar Disorder; Epoetin Alfa; Erythropoietin; Female; Hematologic Neoplasms; Humans; Kidney Transplantation; Lithium; Medical Oncology; Physician-Patient Relations; Recombinant Proteins; Renal Insufficiency, Chronic; Spouses

Topics: Animals; Erythropoietin; Humans; Kidney; Renal Insufficiency, Chronic

Topics: Animals; Erythropoietin; Humans; Kidney; Renal Insufficiency, Chronic

Some chronic hemodialysis (HD) patients can maintain normal hemoglobin levels without requiring erythropoiesis-stimulating agents (ESAs). However, the prevalence and the factors associated with this condition in Chinese chronic HD patients have not been reported. The aim of this study was to investigate clinical features, iron metabolism, and other characteristics to survey the prevalence rate and the related factors of this condition among Chinese chronic HD patients.. A total of 1,318 chronic HD patients participated in this study. The patients were classified into a non-ESA group (n = 11) and an ESA group (n = 1,307). The r-HuEPO-independent (non-ESA) HD patients were defined as having hemoglobin greater than 12 g/dl for more than 6 months without r-HuEPO injection, blood transfusion, or androgen therapy. Epidemiological and laboratory data were collected. Renal sonography was also performed on each patient to evaluate the formation of renal and liver cysts, and the number and size of the cysts were recorded.. Approximately 0.84 % of all HD patients were found to be r-HuEPO independent. The non-ESA group had a higher proportion of men (79.6 vs. 58.3 %), a longer duration of renal replacement therapy (RRT) (8.6 ± 6.1 vs. 5.1 ± 3.3 years), a higher prevalence of adult polycystic kidney disease (APKD) (46.3 vs. 9.7 %), a higher prevalence of hepatitis C virus (HCV) liver disease (26.2 vs. 3.2 %, P < 0.01), and had older patients (63.3 ± 13.6 vs. 49.6 ± 13.5 years). Endogenous erythropoietin levels in the non-ESA group were significantly higher than those in the ESA group (61.8 ± 27.1 vs. 29.3 ± 11.7 mU/ml). Non-ESA patients had a significantly higher number of renal (38.1 vs. 13.2 %) and hepatic cysts (9.3 vs. 1.9 %), which were also larger in size (2.9 ± 1.6 vs. 1.3 ± 0.3 cm) compared with those of patients in the ESA group. No significant difference in iron metabolism was found between two groups. In the multivariate Cox analysis, the independent predictor factors for the absence of anemia in these HD patients were the number of renal cysts >6 cysts (95 % CI 1.058-1.405; P = 0.00), endogenous erythropoietin levels (95 % CI 1.139-1.361; P = 0.05), HCV+ liver disease (95 % CI 1.129-1.316; P = 0.01), and time on RRT (95 % CI 1.019-1.263; P = 0.05).. To our knowledge, this study is the first to report on r-HuEPO independence among Chinese HD patients. The prevalence among Chinese chronic HD patients is significantly lower than that reported in the literature. Factors contributing to this condition are complex and multiple. The frequency of this condition is higher in men and in older patients with long-term RRT, in patients with HCV+ liver disease, and in APKD patients. This condition is associated with increased endogenous erythropoietin production and the presence of renal and hepatic cysts.

Topics: Adult; Age Factors; Aged; Anemia; China; Cross-Sectional Studies; Cysts; Erythropoietin; Female; Hematinics; Hemoglobins; Hepatitis C; Humans; Iron; Liver Diseases; Male; Middle Aged; Polycystic Kidney Diseases; Prevalence; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Ultrasonography

Erythropoiesis-stimulating agents (ESAs) are standard therapy for chronic kidney disease (CKD) patients with renal anemia. However, few studies have compared the effects of different ESAs on anemia in identical pre-dialysis CKD patients.. Seventy-nine patients who switched from epoetin beta to darbepoetin alfa (Group 1), and 82 patients who switched from darbepoetin alfa to epoetin beta pegol (Group 2) were enrolled in this study. Clinical and laboratory parameters were assessed for 6 months before and after switching ESAs. The prevalence of adverse events, the dose conversion ratio of ESAs, and the frequency of ESA administration were also analyzed.. Analysis of variance showed that switching ESAs did not significantly change hemoglobin levels for the study duration in both groups (mean hemoglobin 10.3-10.5 g/dL in Group 1 and 10.4-10.7 g/dL in Group 2). Estimated glomerular filtration rate, blood pressure, transferrin saturation, ferritin, and albumin remained constant in both groups. The prevalence of adverse effects was quite low (0-3.8 %) during both 6-month study periods. The mean dose conversion ratio for epoetin beta:darbepoetin alfa was 163.7 units:1 μg and for darbepoetin alfa:epoetin beta pegol was 1.08 μg:1 μg. The intervals of ESA administration significantly differed (epoetin beta pegol > darbepoetin alfa > epoetin beta).. Epoetin beta, darbepoetin alfa, and epoetin beta pegol are effective and well-tolerated agents for managing anemia in Japanese pre-dialysis CKD patients. The intervals of ESA administration to maintain a patient's target hemoglobin were longer in the order of epoetin beta pegol > darbepoetin alfa > epoetin beta.

Topics: Aged; Aged, 80 and over; Anemia; Cohort Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Japan; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency, Chronic

A 16-year-old vasectomized male ring-tailed lemur (Lemur catta) with a history of suspected chronic renal failure was evaluated because of extreme lethargy, hyperpnea, and abscess of the right pectoral scent gland.. Examination of the anesthetized patient revealed an impacted right pectoral scent gland with serosanguineous exudate. A CBC and serum biochemical analysis revealed severe anemia, marked azotemia, hyperphosphatemia, and hypocalcemia.. Supportive care (including fluid therapy and phosphorus binder administration) was initiated for renal failure; the affected gland was cleaned, and antimicrobials were administered. The patient received 1 blood transfusion, and darbepoetin alfa was administered weekly to stimulate RBC production. Anemia and azotemia persisted. Three months after treatment started, serum iron analysis revealed that iron deficiency was the probable cause for the lack of a consistent regenerative response to darbepoetin injections. Iron dextran injections resulted in a marked regenerative response; however, serum biochemical analysis results after the second injection were consistent with hepatic injury. Hepatic enzyme activities normalized following discontinuation of iron dextran treatment, but the lemur's Hct declined rapidly despite supplementary iron administration PO. The patient developed severe mandibular osteomyelitis and was euthanized because of poor prognosis. Postmortem evaluation of hepatic iron concentration confirmed iron deficiency.. The family Lemuridae is considered prone to hemosiderosis and hemochromatosis, which delayed rapid diagnosis and treatment of the lemur's disease. Apparent hepatic injury following iron dextran injections further complicated treatment. Findings for this lemur support the use of species-specific total iron binding capacity and total serum iron and ferritin concentrations in evaluation of an animal with suspected iron deficiency.

Topics: Aging; Anemia, Iron-Deficiency; Animals; Blood Transfusion; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Dietary Supplements; Erythropoietin; Hematinics; Iron; Iron-Dextran Complex; Lemur; Male; Renal Insufficiency, Chronic

Darbepoetin alfa (DA) is beneficial for pediatric patients for its less injection frequency and greater maximum dose compared to recombinant human erythropoietin. Here, we evaluated pharmacokinetics of DA in Japanese pediatric patients with chronic kidney disease (CKD).. CKD patients (2-18 years old, n = 8 each) received a single dose of body weight adjusted DA either intravenously or subcutaneously.. When administered intravenously, the area under the concentration-time curve from time zero to infinity (AUC0-∞), clearance (CL) and terminal half-life (t 1/2) of DA were 263.7 ng · h/mL, 1.77 mL/h/kg and 26.25 h, respectively (mean). In patients under 12 years old, AUC0-∞, CL and t 1/2 were 219.1 ng · h/mL, 2.19 mL/h/kg, 23.62 h, respectively. These values were mostly similar to those of Japanese adult CKD patients, though AUC0-∞ tended to be lower and CL tended to be higher in the subjects under 12 years old. When administered subcutaneously, time to reach maximum concentration (t max) and maximum concentration (C max) were 24.47 h and 1.704 ng/mL, and AUC0-∞, apparent clearance (CL/F) and t 1/2 were 141.1 ng · h/mL, 3.23 mL/h/kg and 46.73 h, respectively. In patients under 12 years old, t max and C max were 7.50 h and 2.053 ng/mL, and AUC0-∞, CL/F and t 1/2 were 136.7 ng · h/mL, 3.29 mL/h/kg and 37.75 h, respectively, which was higher in C max, faster in t max and shorter t 1/2 compared to adult CKD patients, while AUC was not obviously different.. The pharmacokinetics of DA in pediatric CKD patients is not obviously different from those in adult.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Japan; Male; Middle Aged; Renal Insufficiency, Chronic; Treatment Outcome

Anemia and chronic kidney disease are common disorders in heart failure (HF) patients and are associated with increased morbidity and mortality. This study assessed clinical outcomes associated with erythropoietin (EPO) treatment in this cardiorenal anemia syndrome (CRAS) population.. This was a retrospective cohort study of Veterans Affairs patients with CRAS from January 2003 to December 2006. The primary outcome was a composite of death, acute coronary syndrome (ACS), HF, and stroke. Multiple Cox regression modeling was used to evaluate the outcome in patients prescribed (n = 213) and not prescribed EPO (n = 1845). Adjusted incidence of mortality was statistically significantly higher in EPO than in non-EPO users (33.8% vs 19.7%; hazard ratio 1.40, 95% confidence interval 1.06-1.85; P = .02). The unadjusted composite of cardiovascular events/death was higher in the EPO group, but not statistically significant when adjusted for confounders (P = .12). Crude ACS events were documented in 18.8% and 10.8% patients (P = .001), and stroke events occurred in 22.5% and 18.3% patients (P = .14) in EPO and non-EPO groups, respectively.. We found that in CRAS patients, EPO use was associated with increased risk of mortality and a trend toward increased cardiovascular events. Therefore, clinicians considering EPO use in CRAS patients should assess whether any potential benefits outweigh the risks of use.

Topics: Aged; Aged, 80 and over; Anemia; Cohort Studies; Disease-Free Survival; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

Anemia is common in patients with advanced chronic kidney disease. Whereas the treatment of anemia in patients with end-stage renal disease (ESRD) has attracted considerable attention, relatively little is known about patterns and trends in the anemia care received by patients before they start maintenance dialysis or undergo preemptive kidney transplantation.. To determine the trends in anemia treatment received by Medicare beneficiaries approaching ESRD.. Closed cohort study in the United States using national ESRD registry data (US Renal Data System) of patients 67 years or older who initiated maintenance dialysis or underwent preemptive kidney transplantation between 1995 and 2010. All eligible patients had uninterrupted Medicare (A+B) coverage for at least 2 years before ESRD.. Time, defined as calendar year of incident ESRD.. Use of erythropoiesis-stimulating agents (ESA), intravenous iron supplements, and blood transfusions in the 2 years prior to ESRD; hemoglobin concentration at the time of ESRD. We used multivariable modified Poisson regression to estimate utilization prevalence ratios (PRs).. Records of 466,803 patients were analyzed. The proportion of patients with incident ESRD receiving any ESA in the 2 years before increased from 3.2% in 1995 to a peak of 40.8% in 2007; thereafter, ESA use decreased modestly to 35.0% in 2010 (compared with 1995; PR, 9.85 [95% CI, 9.04-10.74]). Among patients who received an ESA, median time from first recorded ESA use to ESRD increased from 120 days in 1995 to 337 days in 2010. Intravenous iron administration increased from 1.2% (1995) to 12.3% (2010; PR, 9.20 [95% CI, 7.97-10.61]). The proportion of patients receiving any blood transfusions increased monotonically from 20.6% (1995) to 40.3% (2010; PR, 1.88 [95% CI, 1.82-1.95]). Mean hemoglobin concentrations were 9.5 g/dL in 1995, increased to a peak of 10.3 g/dL in 2006, and then decreased moderately to 9.9 g/dL in 2010.. Between 1995 and 2010, older adults approaching ESRD were increasingly more likely to be treated with ESAs and to receive intravenous iron supplementation, but also more likely to receive blood transfusions.

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Cohort Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobin A; Humans; Incidence; Iron; Kidney Failure, Chronic; Medicare; Practice Patterns, Physicians'; Recombinant Proteins; Registries; Renal Insufficiency, Chronic; United States

Chronic kidney disease (CKD) patients on dialysis regularly receive erythropoiesis stimulating agent (ESA) for treating renal anaemia during their dialysis unlike those who are not on dialysis. In such patients, the longer acting ESA can be helpful in reducing their frequent visits to the health care facilities and improving their compliance. This study was aimed to examine the efficacy and safety of continuous erythropoietin receptor activator (CERA), a long acting ESA in treating renal anaemia in patients with diabetic CKD not on dialysis.. In this prospective, open-labelled, pilot clinical study, 35 adult type 2 diabetes patients with nephropathy and renal anaemia, who were not on dialysis nor receiving treatment with ESA were administered CERA subcutaneously once in two weeks for a period of 24 weeks. The primary efficacy end point was to evaluate the Hb response (Hb rise of ≥1 g/dl above the baseline or Hb level ≥11 g/dl) during the study period.. All patients showed Hb rise ≥1 g/dl during the study period and 80 per cent patients could achieve Hb value ≥11 g/dl. The maximum median Hb rise of 1.2 g/dl occurred in the initial 6 weeks after starting the treatment. The mean creatinine clearance (CrCl) improved by 2.8 ml/min, with mean Hb rise of 2.6 g/dl from the baseline after administration of CERA. Worsening of blood pressure (BP) control (42.9%) was the most common adverse event.. CERA once in two weeks was found to be efficacious in correcting anaemia in the ESA-naïve patients with diabetic nephropathy who are not on dialysis. However, regular monitoring of blood pressure is required while on treatment with CERA.

Topics: Adult; Anemia; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Ever since the introduction of EPO, ESAs and iron dosing have been driven by financial incentives. When ESAs were a profit center for providers, large doses were used. With ESAs becoming a cost center, a new trend has appeared, gradually replacing their use with iron to achieve the same therapeutic effect at lower cost. This financially driven approach, treating ESAs and iron as alternatives, is not consistent with human physiology where these agents act in a complementary manner. It is likely that we are still giving unnecessarily large doses of ESAs and iron, relative to what our patients' true needs are. Although we have highlighted the economic drivers of this outcome, many other factors play a role. These include our lack of understanding of the complex interplay of the anemia of chronic disease, inflammation, poor nutrition, blood loss through dialysis, ESAs and iron deficiency. We propose that physiology-driven modeling may provide some insight into the interactions between erythropoiesis and ferrokinetics. This insight can then be used to derive new, physiologically compatible dosing guidelines for ESAs and iron.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Hematinics; Humans; Iron; Prospective Payment System; Renal Dialysis; Renal Insufficiency, Chronic

Hemoglobin variability (Hb-var) in patients with chronic kidney disease has been stipulated to be a result of exogenous treatment with erythropoiesis stimulating agents (ESA) and has been related to mortality in dialysis patients. We hypothesized the existence of Hb-var independent of ESA administration and compared it to that in healthy adults using data from the Scripps-Kaiser and NHANES III databases. We studied the Hb-var in 1571 peritoneal dialysis patients which included 116 patients not requiring treatment with erythropoietin. We systematically studied the differences between the groups that needed ESA therapy and those who did not. White race and male sex were significant predictors of need for erythropoietin therapy. We found peritoneal dialysis patients to exhibit significantly increased Hb-var independent of treatment with exogenous erythropoietin (0.99 gm/dL vs. 1.17 gm/dL, p-value<0.001). We found age to be a significant determinant of Hb-var in the ESA treated group. Hb-var in younger patients (<30 years) was increased by 50% compared to young healthy adults. The Hb-var in elderly (>60 years) peritoneal dialysis patients was similar to that seen in healthy elders, suggesting similarity with anemia of aging. We conclude that exogenous ESA administration does not explain Hb-var entirely but may enhance it. Intrinsic factors affecting erythropoiesis including age may be the major determinants of Hb-var.

Topics: Adult; Aged; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Sex Factors; White People

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub-cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability-weighted (IPW) analysis to adjust for time-dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time-dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223-0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53-0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.

Topics: Aged; Aged, 80 and over; Anemia; Cohort Studies; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Japan; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Animals; Cytomegalovirus; Erythropoietin; Humans; Renal Insufficiency, Chronic

Anemia is a feature of CKD and a complication of renal transplantation, often caused by impaired production of erythropoietin. The kidney is a target organ for human cytomegalovirus (hCMV) in such patients, but it is not known whether hCMV effects erythropoietin production. We found that kidneys from patients with CKD were positive for hCMV protein and that blood levels of hCMV IgG inversely correlated with red blood cell count. In mice, systemic murine cytomegalovirus infection decreased serum erythropoietin levels. In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultraviolet-inactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxia-inducible transcription factor (HIF)-1α and HIF2α, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2α mRNA. HIF2α is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2α was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients.

Topics: Animals; Antibodies, Viral; Basic Helix-Loop-Helix Transcription Factors; Cell Culture Techniques; Cell Hypoxia; Cytomegalovirus; Erythrocyte Count; Erythropoietin; Hemoglobins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoglobulin G; Mice; Renal Insufficiency, Chronic; RNA, Messenger

Higher doses of erythropoiesis-stimulating agents (ESA) have been associated with an increased risk of adverse outcomes in adults with chronic kidney disease (CKD) and end-stage kidney disease (ESRD), but to our knowledge no trials have been performed in children. We examined the association between ESA dose and all-cause mortality in a prevalent pediatric dialysis population.. Retrospective cohort study utilizing national data on all prevalent dialysis patients aged <18 years from the Centers for Medicare and Medicaid Services' 2005 ESRD Clinical Performance Measures (CPM) project, linked to 18-month mortality records from the United States Renal Data System. Multivariate Cox proportional hazards regression was performed to determine the risk of mortality by mean weekly ESA dose.. Eight-hundred and twenty-nine children were included in the analysis; 7 % died during follow-up. A higher proportion of patients receiving ESA doses in the highest category (erythropoietin ≥350 units/kg/week or darbepoetin ≥1.5 units/kg/week) died (50 % vs 28 %, p = 0.002), and also demonstrated a trend toward lower hemoglobin (11.0 vs 11.4 g/dL, p = 0.05). In multivariate analysis, patients receiving the highest dose of ESA demonstrated an increased risk of mortality (hazard ratio 3.37; p value <0.01).. Higher ESA dose is independently associated with mortality in children on chronic dialysis.

Topics: Child; Cohort Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies

Anemia management clinics have demonstrated favorable impacts on clinical and economic outcomes and patient satisfaction. Clinical pharmacists are uniquely qualified to manage complex drug therapies requiring intensive monitoring. The complexity, risks associated with inappropriate treatment, and high cost of erythropoietin-stimulating agents (ESAs) make patients on these medications excellent candidates for clinical pharmacist-based management. Integrating ESA management into a clinical pharmacist-managed service has the potential to improve anemia management not only by improving patient outcomes and patient safety, but also by decreasing medication costs.. To (a) assess adherence to monitoring guidelines, efficacy, and safety outcomes and (b) quantify medication utilization expenditures among patients using ESA therapy managed by a clinical pharmacy service compared with usual care.. This is a retrospective longitudinal cohort study of patients with anemia caused by chronic kidney disease who were on ESA treatment for at least 6 months between January 2008 and December 2010. Adherence to monitoring guidelines, efficacy, safety, and drug utilization outcomes were compared between the 2 groups.. A total of 101 patients were included in the study. Of that number, 31 were managed by the pharmacist-managed anemia service, and 70 were in the usual care group. The pharmacist-managed patients had improved adherence to guidelines for hemoglobin monitoring (32.3% vs. 14.3%, P = 0.049) and iron monitoring (61.3% vs. 30.0%, P = 0.005) compared with similar patients receiving usual care. Time to achievement of hemoglobin target was 28 days in the pharmacist-managed group compared with 41 days in the usual care group (P = 0.135), while the proportion of patients achieving target hemoglobin was 96.8% compared with 95.7%, respectively (P = 0.654). Patients in the pharmacist-managed group used less epoetin alfa during the 6-month period, leading to an annualized savings of $1,288 per patient in drug expenditures. . A clinical pharmacist-managed anemia service resulted in improved adherence to national monitoring guidelines, equivalent quality and safety outcomes, and lower medication utilization compared with usual care. 

Topics: Aged; Aged, 80 and over; Anemia; Cohort Studies; Drug Monitoring; Epoetin Alfa; Erythropoietin; Female; Guideline Adherence; Hematinics; Humans; Longitudinal Studies; Male; Middle Aged; Pharmacists; Pharmacy Service, Hospital; Practice Guidelines as Topic; Professional Role; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies

In a landmark study, TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) examined the use of erythropoiesis-stimulating agent (ESA) therapy to treat anemia among patients with chronic kidney disease (CKD) and found no benefit compared to placebo.. A retrospective observational design was used to determine the impact of TREAT on clinical practice.. A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and 4.. ESA prescribing 2 years before and after publication of TREAT.. Rate of ESA prescribing for ESA-naive and -prevalent cohorts.. (1) Monthly ESA prescribing in the 2 years before and after publication of TREAT (ordinary least squares regression), (2) adjusted likelihood of prescribing ESA after TREAT (clustered logistic regression), and (3) probability of receiving ESA therapy based on anemia status (χ(2) test).. For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage 3: change of slope, -0.08 [P<0.001]; stage 4: change of slope, -0.16 [P<0.001]). ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin levels <10g/dL, only 25% of patients with CKD stage 3 and 33% of patients with stage 4 were prescribed ESAs 2 years after TREAT, a notable 50% decline. After adjusting for all covariates, the probability of prescribing ESAs was 35% lower during the 2-year period after versus before publication of TREAT (OR, 0.65; 95% CI, 0.63-0.67).. The cumulative effect of adverse safety concerns in the period before TREAT also influenced physician prescribing of ESA therapy and could not be separated from the influence of TREAT.. TREAT appears to be a watershed study that was followed by a marked decline in ESA prescribing for patients with CKD.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Darbepoetin alfa; Databases, Factual; Erythropoiesis; Erythropoietin; Female; For-Profit Insurance Plans; Humans; Male; Medicare; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome; United States

To assess whether the correction dose recommended by the summary of product characteristics was adequate and to confirm the adequacy of the recommended conversion dosing strategies from shorter-acting erythropoiesis-stimulating agents (ESAs) to continuous erythropoietin receptor activator (C.E.R.A) in anaemic chronic kidney disease (CKD) patients in the clinical setting.. This was a 12-month, multicenter, prospective, observational study in anaemic CKD patients on haemodialysis and not on dialysis receiving C.E.R.A (at least one dose).. A total of 227 patients were included (not on dialysis; n = 142; haemodialysis: n = 85). The present analysis was conducted on ESA-naïve patients (not on dialysis: n = 31) and patients switched from other ESA (not on dialysis: n = 63; haemodialysis: n = 57). Both on and not on dialysis patients switched from other ESA received lower starting C.E.R.A doses than those recommended, and remained stable during the 12-month period. The higher the previous ESA dose was, the more beneficial the C.E.R.A dose conversion factor was. The proportion of patients with stable haemoglobin within the target range (11-13 g/dL) did not vary during the 12-month period both in nondialysis CKD patients and in those undergoing dialysis [baseline: 42 (66.7 %) and 34 (59.6 %); month 6: 21 (55.3 %) and 26 (50.0 %); month 12: 20 (64.5 %) and 25 (69.4 %), respectively]. In naïve patients, the mean weight-adjusted C.E.R.A dose during the study (1.19 ± 0.49 µg/kg/month) was similar to the recommended one. C.E.R.A was well tolerated.. Conversion from shorter-acting ESAs to C.E.R.A doses lower than those recommended can efficiently maintain target haemoglobin levels both in nondialysis and haemodialysis CKD patients, particularly when switching from higher ESA doses. A monthly C.E.R.A dose of 1.2 µg/Kg seems adequate for anaemia correction.

Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Spain; Treatment Outcome

Topics: Administration, Oral; Anemia; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Humans; Infusions, Intravenous; Iron; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

There is scant real-world information on switching treatment for anemia associated with chronic kidney disease (CKD) from methoxy polyethylene glycol-epoetin beta (PEG-Epo) to darbepoetin alfa (DA). TRANSFORM was a multi-center, observational study designed to describe the time course of hemoglobin (Hb) concentration (primary outcome measure) and other parameters of clinical management of anemia in European hemodialysis patients in clinical practice before and after a switch from PEG-Epo to DA.. Eligible subjects were adult patients with CKD dialyzed at European dialysis centers for ≥26 weeks and treated with PEG-Epo for ≥14 weeks immediately prior to being switched to DA and no earlier than January 2011. Erythropoiesis-stimulating agent doses and Hb values were recorded for the 14-week pre-switch and 26-week post-switch periods.. Of the 1,027 eligible patients enrolled at 42 hemodialysis centers in 7 European countries, 785 were included in analyses. Mean (95% confidence interval [CI]) Hb was generally stable: 11.19 (11.11, 11.26), 11.48 (11.40, 11.57), and 11.29 (11.20, 11.37) g/dL at month -1 pre-switch and months 3 and 6 post-switch, respectively. The geometric mean (95% CI) PEG-Epo dose at month -1 was 27.4 (26.0, 28.8) µg/week; DA dose was 29.4 (27.9, 30.9), 23.3 (21.9, 24.9), and 25.6 (24.1, 27.1) µg/week at months 1, 4, and 6, respectively. The geometric mean (95% CI) dose ratio at switching was 1.06 (1.01, 1.11). When stratifying by dose-ratio categories <0.8, 0.8-1.2, and >1.2 at switching, mean DA dose and Hb converged within narrow ranges by month 6 post-switch: 23.9-27.0 µg/week and 11.1-11.5 g/dL, respectively. Hb excursions <10 g/dL were less frequent post-switch versus pre-switch.. Mean Hb values remained within a narrow range following switching from PEG-Epo to DA in this population of hemodialysis patients. Time trends of mean Hb and DA dose indicate that physicians titrated DA doses post-switch, to attain Hb concentrations comparable to those attained pre-switch with PEG-Epo.

Topics: Adult; Aged; Anemia; Darbepoetin alfa; Drug Substitution; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Longitudinal Studies; Male; Middle Aged; Outcome Assessment, Health Care; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

Topics: Anemia; Animals; Erythropoietin; Female; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Macaca fascicularis; Male; Pyrazoles; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Triazoles; Up-Regulation

The significance of glycated albumin (GA) compared with casual plasma glucose (PG) and glycated hemoglobin (HbA1c) was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. In HD patients with diabetes (n = 25), the mean PG, GA and HbA1c levels were 192.9 + 23 mg/dL, 278.8 + 43 μmol/L and 5.9 + 0.5%, respectively, which were higher by 43.9%, 67.04% and 18%, respectively, compared with HD patients without diabetes (n = 25). HbA1c levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the three parameters in patients who had diabetes without renal dysfunction (n = 25). A significant negative correlation was found between GA and serum albumin (r = 0.21, P <0.05) in HD patients with diabetes, whereas HbA1c correlated positively and negatively with hemoglobin (r = 0.11, P <0.01) and weekly dose of erythropoietin injection (r = -0.19, P < 0.01), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA1c levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartiles by GA level led to better glycemic control in a significantly higher proportion of HD patients with diabetes than those assessed by HA1c. Multiple regression analysis demonstrated that hemoglobin in addition to PG emerged as an independent factor associated with HbA1c in HD patients with diabetes, while PG, body mass index and albumin were an independent factor associated with GA.. it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA1c in these patients might lead to likely underestimation as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Topics: Adult; Anemia; Biomarkers; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Egypt; Erythropoietin; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Hypoglycemic Agents; Kidney; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Renal Dialysis; Renal Insufficiency, Chronic; Reproducibility of Results; Serum Albumin; Time Factors

Recent studies have raised concern about the safety of erythropoiesis-stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m(2)) aged 63±13 years.. Arteries were mounted on a pressurized myograph. EPO impaired endothelium-dependent relaxation in a concentration-dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P<0.001). EPO-induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine-induced vasoconstriction or sodium nitroprusside-induced relaxation. ABT-627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO (P<0.01). Increased expression of endothelin-1 was found in the vessel wall after incubation with EPO.. EPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO-induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials.

Topics: Acetylcholine; Aged; Anemia; Arteries; Buttocks; Carotid Arteries; Carotid Intima-Media Thickness; Endothelin-1; Endothelium, Vascular; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Pulse Wave Analysis; Recombinant Proteins; Renal Insufficiency, Chronic; Vasodilator Agents

Topics: Anemia; Erythropoietin; Female; Hematinics; Humans; Male; Peptides; Renal Insufficiency, Chronic

Topics: Anemia; Erythropoietin; Female; Hematinics; Humans; Male; Peptides; Renal Insufficiency, Chronic

Some publications have shown that equivalent doses of erythropoiesis-stimulating agents (ESA) defined on label differ from those effective in clinical practice. Therefore, real costs could vary from theoretical costs in the treatment of anaemia in chronic kidney disease (CKD).. To perform a cost-minimization analysis to establish the economic impact of the principal ESAs used in treating anaemia secondary to CKD in daily practice.. to determine patient-month cost based on the erythropoietin resistance index (ERI); to analyze the difference in cost between pre-dialysis and peritoneal dialysis (PD) patients; and to analyze the association between iron deposits and ESA cost.. This study was carried out at 2 tertiary hospitals in Spain.. A multicentre cost-minimization analysis was performed in adult outpatients treated with ESAs for anaemia due to CKD.. The primary outcome was the patient-month cost for each ESA.. 409 patients were included. Median patient-month cost was: epoetin (103.2 [63.7, 187.8] euros), darbepoetin α (134.4 [67.2, 216.0] euros) and CERA (147.5 [98.3, 196.7] euros). Median patient-month cost according to ERI was: epoetin (1.60 [0.90, 2.60] euros/kg), darbepoetin α (2.01 [0.95, 3.48] euros/kg) and CERA (1.87 [1.33, 3.00] euros/kg). Median patient-month cost in pre-dialysis was 126.0 (73.7, 201.6) euros and in PD 153.0 (100.2, 275.4) euros. Median patient-month cost for patients with TSI < 20% was 147.5 (98.3, 224.9) euros compared to 100.9 (67.2, 196.7) euros which was the cost for patients with IST ≥ 20%. The median patient-month cost for patients with ferritin < 100 mcg/l was 134.4 (85.0, 201.6) euros compared to 100.8 (68.8, 196.7) euros, which was the cost for patients with ferritin ≥ 100 mcg/l (p = 0.242).. Doses of CERA used in clinical practice are lower than those recommended on label, which directly influences cost and treatment efficiency. Cost stratification based on iron deposits has shown that patients with low TSI or ferritin require higher doses and consequently an associated higher cost. Thus, to guarantee adequate iron levels is essential in the rational use of ESAs.

Topics: Aged; Aged, 80 and over; Anemia; Costs and Cost Analysis; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Costs; Drug Labeling; Erythropoietin; Female; Hematinics; Humans; Iron; Male; Middle Aged; Outpatients; Peritoneal Dialysis; Polyethylene Glycols; Renal Insufficiency, Chronic; Spain; Tertiary Care Centers

Topics: Anemia; Animals; DNA; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Renal Insufficiency, Chronic

Attempts to achieve near-normal hemoglobin levels have been associated with higher mortality among chronic kidney disease patients. Evidence suggests a higher mortality rate for those with resistance to erythropoietin-stimulating agents (ESA). We investigated the association between responsiveness to ESA, dose of ESA and mortality in our hemodialysis population.. A retrospective cohort study of chronic hemodialysis patients receiving dialysis was conducted at the University of Virginia facilities. We collected data on patient demographics, comorbidities, dialysis vintage, vascular access type, body weight, ESA dose and hemoglobin, as well as data on known risk factors for ESA hyporesponsiveness. Vital status was determined 30 months later. The association between ESA responsiveness and mortality was investigated by using the Cox proportional hazard model adjusting for demographics, comorbidities, access type, dialysis adequacy, serum albumin, serum parathyroid hormone and ferritin concentrations.. A total of 606 patients were included. The overall 30-month mortality was 35.8%. Compared to those in the lowest tertile of ESA hyporesponsiveness, patients in the middle and upper tertiles had significantly higher mortality (hazard ratio, HR: 1.64, 95% CI: 1.14-2.37, and HR: 2.08, 95% CI: 1.46-2.97, respectively). In the Cox proportional hazard model each unit increment in the ESA resistance index was associated with an HR of 2.27 (95% CI: 1.60-3.23) for mortality. In this model each 1-unit increment in ESA dose/kg or each 100-μg increment in absolute darbepoetin alfa dose were associated with a 9% increased risk of mortality (HR: 1.09, 95% CI: 1.04-1.13, and HR: 1.09, 95% CI: 1.03-1.15, respectively).. Among prevalent hemodialysis patients, a higher degree of resistance to and higher doses of ESA are associated with increased mortality.

Topics: Aged; Anemia; Cause of Death; Comorbidity; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

HbA(1c) values are unreliable in patients with diabetes who have chronic kidney disease who receive iron and/or erythropoiesis stimulating agents. The study aimed to evaluate the utility of the complementary glycaemic markers glycated albumin, fructosamine and 1,5 anhydroglucitol in this group of patients.. A prospective study of patients with Type 2 diabetes and chronic kidney disease stage IIIB/IV undergoing intravenous iron or erythropoiesis-stimulating agent therapy. Glycaemic control was monitored using HbA(1c), seven-point daily glucose thrice weekly, continuous glucose monitoring, glycated albumin, fructosamine and 1,5 anhydroglucitol.. Fifteen patients [9 men; median age 72 years (interquartile range 68-74), follow-up period (16.4 ± 3.7 weeks)] received parenteral iron; 15 patients [11 men; 70 years (interquartile range 62-75), (17.3 ± 3.3 weeks)] received erythropoiesis-stimulating agent. HbA(1c) fell following treatment with both iron [57 mmol/mol (7.4%) to 53 mmol/mol (7.0%), P < 0.001] and erythropoiesis-stimulating agent [56 mmol/mol (7.3%) to 49 mmol/mol (6.6%), P = 0.01] despite mean blood glucose remaining unchanged (iron: 9.55 to 9.71 mmol/l, P = 0.07; erythropoiesis-stimulating agent: 8.72 to 8.78 mmol/l, P = 0.89). Unlike HbA1c , the glycated albumin, fructosamine and 1,5 anhydroglucitol levels did not change following iron [glycated albumin (16.8 to 16.3%, P = 0.10); fructosamine (259.5 to 256 μmol/l, P = 0.89); 1,5 anhydroglucitol (54.2 to 50.9 μmol/l, P = 0.89)] or erythropoiesis-stimulating agent [glycated albumin (17.9 to 17.5%, P = 0.29), fructosamine (324.3 to 306.0 μmol/l, P = 0.52), 1,5 anhydroglucitol (58.2 to 46.7 μmol/l, P = 0.35)]. Despite this, HbA(1c) was consistently the marker most closely related to mean blood glucose before and after each treatment (R range 0.7-0.88).. These data indicate that HbA(1c) was statistically most closely related to mean blood glucose, but clinical trends in glycaemia in patients undergoing iron or erythropoiesis-stimulating agent therapy are likely best assessed by including one of these additional glycaemic markers.

Topics: Administration, Intravenous; Aged; Biomarkers; Blood Glucose; Delivery of Health Care; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Fructosamine; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Iron; Male; Monitoring, Physiologic; Prospective Studies; Recombinant Proteins; Renal Insufficiency, Chronic; Serum Albumin; Severity of Illness Index; Time Factors; Treatment Outcome

Topics: Anemia; Erythropoietin; Female; Hematinics; Humans; Male; Peptides; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFκB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFκB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFκB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.

Topics: Anemia; Animals; DNA Modification Methylases; Erythropoietin; Kidney; Mice; Mice, Knockout; Myofibroblasts; Nephrosclerosis; NF-kappa B; Phenotype; Renal Insufficiency, Chronic; Ureteral Obstruction

Topics: Anemia; Erythropoietin; Hematinics; Humans; Renal Insufficiency, Chronic

Topics: Anemia; Drug Monitoring; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Topics: Anemia; Erythropoietin; Hematinics; Hemoglobins; Humans; Patient-Centered Care; Renal Insufficiency, Chronic

Topics: Anemia; Drug Monitoring; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Topics: Anemia; Computers; Decision Support Systems, Clinical; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Hematinics; Humans; Iron; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Trace Elements

Long or frequent hemodialysis schedules are reported to improve clinical outcomes. We report here our experience with an in-center, nocturnal, thrice-weekly hemodialysis program. We retrospectively analyzed the effect of switching 10 patients (8 male, age 45 ± 11 years, renal replacement therapy vintage 12 ± 8 years) from regular, 4-5 h, thrice-weekly hemodialysis to 8 h nocturnal, in-center hemodialysis as regards dialysis efficiency, chronic kidney disease-metabolic and bone disease (CKD-MBD) parameters, blood pressure, and anemia. With more intense dialysis, the mean predialysis creatinine and urea decreased significantly (1092 ± 195 vs. 961 ± 154 μmol/L, P < 0.01 and 30.8 ± 4.6 vs. 25.5 ± 2.9 mmol/L, P < 0.01), while the decrease in potassium was insignificant (5.9 ± 0.7 vs. 5.6 ± 0.5 mmol/L), but in 3/10 patients, dialysate potassium was increased. Three months after starting nocturnal hemodialysis, no significant influence on pre-dialysis blood pressure was observed (143/80 vs. 140/80 mmHg), but antihypertensive medications were reduced in two patients. The mean dry weight reduced (74 ± 12 to 72 ± 12 kg) and the mean ultrafiltration increased insignificantly (3123 ± 1174 to 3434 ± 1341 mL). Serum calcium was stable, while phosphate reduced insignificantly (1.5 ± 0.5 to 1.2 ± 0.2 mmol/L), but 6/10 patients were able to discontinue phosphate binders, the dose was reduced in one, and phosphate was added to dialysate in 3/10 patients. Intact parathyroid hormone values were within the target range, except in patients post-parathyroidectomy. There were no differences in hemoglobin (121 ± 6 vs. 122 ± 8 g/L), and the mean epoetin dose decreased insignificantly (5950 ± 3947 vs. 5250 ± 4238 IU/week). To conclude, improved phosphate and potassium control and reduction in phosphate binders were observed after switching to nocturnal hemodialysis. There was an insignificant reduction of epoetin dose and antihypertensive medications.

Topics: Adult; Antihypertensive Agents; Bone Diseases, Metabolic; Chelating Agents; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Phosphates; Polyethylene Glycols; Potassium; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Time Factors; Treatment Outcome

In non-dialysis patients (ND-CKD), C.E.R.A. has been extensively investigated in ESA-naïve subjects but no data are available on its efficacy after switch from other ESA.. In this prospective, multicenter, open-label study lasting 24 weeks, ND-CKD patients (n = 157) receiving ESA were converted to C.E.R.A. at doses lower than recommended. Primary outcome was the prevalence of Hb target (11-12.5 g/dl).. Age was 73 ± 13 years and GFR was 26.2 ± 9.4 ml/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 49, 33 and 19%, respectively. Doses of darbepoetin (25 ± 16 µg/week, n = 124) and epoetin (5,702 ± 3,190 IU/week, n = 33) were switched to low dose C.E.R.A. (87 ± 17 µg/month). During the study, prevalence of Hb target increased from 60% to 68% at week-24, while that of Hb < 11 g/dl declined from 32% to 16% (p < 0.001). Hb increased from 11.3 ± 0.8 at baseline to 11.7 ± 0.9 g/dl at week-24 (p = 0.01) without changes in C.E.R.A. dose. Significant predictors of Hb increase were low BMI, low Hb and longer dosing intervals before switch. These factors also predicted the risk of Hb overshooting (Hb > 12.5 g/dl) occurring in 57 patients.. In ND-CKD, conversion from other ESAs to C.E.R.A. is associated with a better anemia control induced by a greater Hb increase in patients previously treated with ESAs at extended dosing interval. This parameter should be considered when switching to long-acting ESA for its potential impact on the risk of overshooting.

Topics: Aged; Aged, 80 and over; Drug Substitution; Erythrocyte Indices; Erythropoietin; Female; Humans; Male; Middle Aged; Peptides; Prospective Studies; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Topics: Animals; Erythropoietin; Nephrosclerosis; Renal Insufficiency, Chronic

The purpose of this study is to identify whether hemoglobin (Hb) concentrations can be maintained, and to investigate changes in biomarkers, when switching from erythropoietin stimulating agents (ESA) with shorter half-life to once-monthly subcutaneous methoxy polyethylene glycol-epoetin β (CERA) in pre-dialysis chronic kidney disease (CKD) patients.. Pre-dialysis CKD patients (n=191) aged ≥18 years who maintained their Hb level 10-12 g/dL through use of epoetin-α, epoetin-β, or darbepoetin-α were enrolled. Hb levels and CERA dose was assessed prospectively for 24 weeks. Serum biomarkers related to coagulation, endothelial function, and iron metabolism were measured at weeks 0 and 24.. Baseline Hb concentration was 10.8±0.6 g/dL Twelve and 24 weeks after conversion, mean Hb levels were 11.9±0.9 and 11.2±0.9 g/dL, respectively. The mean monthly CERA dose required to maintain Hb levels was gradually reduced. Of total 387 dose adjustments, dose increases and decreases occurred in 35 (9.0%) and 352 (91.0%) episodes, respectively. Hb overshoot occurred in 14 (9.7%) patients. P-selectin was significantly decreased, whereas VCAM was significantly increased 24 weeks after conversion (P < 0.05). Serum soluble transferrin receptor E-selectin and prohepcidin levels were similar before and after switching to CERA (P=N-S).. Conversion from ESA with shorter half-life to subcutaneous once-monthly CERA in pre-dialysis CKD patients can efficaciously maintain Hb. The CERA dose requirement decreased significantly. The conversion ratio may need to be reduced when switching from ESA with shorter half-life to CERA. CERA may change biomarkers associated with platelet reactivity and endothelial microenvironment.

Topics: Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Half-Life; Hemoglobins; Humans; Injections, Subcutaneous; Male; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

To search whether calcium channel blockers (CCBs) are associated with lower hemoglobin levels in chronic kidney disease (CKD) patients who are not on renal replacement therapy (RRT), vitamin D and anti-anemic treatment.. CKD patients were classified into two groups. Patients on CCBs treatment (103 patients) and patients not using CCBs (104 patients) were compared cross-sectionally regarding clinical findings, complete blood count (CBC), biochemistry and regular medication use. Patients with polycystic kidney disease, comorbidities that could influence CBC other than iron deficiency of obscure origin, patients receiving RRT, erythropoietin (EPO), vitamin D, phosphate binders and drugs that could influence CBC were excluded. Under dependent variable of CCB use, all significantly different independent variables were subjected to multivariate binary logistic regression analysis (MBLRA).. Lower hemoglobin, lower bilirubinemia, higher serum EPO, higher systolic blood pressure were observed in CCB users. Two groups were similar concerning age, gender, BMI, CKD etiology, CKD stage, pretibial edema prevalence, cardiothoracic index, diastolic blood pressure, corrected reticulocyte count, BUN, creatinine, eGFR, proBNP, parathormone, alkaline phosphatase, phosphorous, corrected calcemia, sCRP, relative EPO deficiency and prevalence of relative EPO deficient patients. Groups were comparable regarding comorbidities, types and usage frequencies of all antihypertensive medications other than CCBs. Higher systolic blood pressure and lower hemoglobin were significantly associated with CCB use after MBLRA.. Hemoglobin was significantly lower in CCB users compared to non-users, among CKD patients who did not receive RRT, EPO, phosphate binders, vitamin D, iron, vitamin B12 and folic acid.

Topics: Adult; Aged; Aged, 80 and over; Calcium Channel Blockers; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Renal Insufficiency, Chronic

Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement.. We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from ≥6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID.. Age was 69 ± 13 years and GFR 27.5 ± 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively).. This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment.

Topics: Aged; Anemia; Dietary Supplements; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Italy; Male; Prevalence; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic

Hyporesponsiveness to a large dose of erythropoietin-stimulating agents (ESA) could increase mortality risk among chronic kidney disease patients. This study aimed to assess a safe dose of ESA and the impact of hyporesponsiveness to ESA on mortality risk among hemodialyzed patients.. Patients on hemodialysis were enrolled in this cohort study. The first year was used to assess the longitudinal dialysis status of patients; the subsequent 2 years were used to assess the time-dependent risk of mortality.. Of the 349 subjects enrolled, 40 died within 2 years. When subjects were stratified by epoetin dose and hemoglobin level into four groups, those who had low hemoglobin despite a high dose of epoetin were associated with the highest risk of mortality among the four groups (adjusted hazard ratio 2.73; 95 % confidence interval 1.20-6.24). These highest-risk subjects had lower serum albumin and higher serum ferritin than any of the other subjects. The impact of serum albumin and serum ferritin on mortality risk in an unadjusted Cox proportional hazards model was attenuated in an adjusted model which included factors of low hemoglobin and higher ESA. A dose of epoetin up to 9000 U/week had no impact on mortality risk as long as hemoglobin levels stayed above 10 g/dL.. Hyporesponsiveness to ESA was associated with an increased risk of mortality. There was no sign of increased mortality risk associated with epoetin itself up to a total dose of 9000 U/week.

Topics: Aged; Anemia; Biomarkers; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Serum Albumin; Serum Albumin, Human; Time Factors; Treatment Outcome

There are concerns that biosimilar erythropoiesis-stimulating agents (ESAs) are less effective than the originator ESAs. The objective of our study was to investigate differences between originator and biosimilar ESA utilisation based on defined daily doses (DDD), doses upon switching, differences between short- and long-acting ESAs and prescribed daily doses (PDD) of either ESA in ambulatory patients with renal anaemia undergoing chronic maintenance haemodialysis [chronic kidney disease (CKD) stage 5].. Patients with CKD stage 5 and specific pharmacotherapy with ESAs for at least six 3-month periods (accounting quarters) were selected from a population-based database of accounting information of Bavarian physicians and pharmacy claims data (January 2008 to December 2010). The DDD was used to determine mean ESA consumption. Descriptive statistics were used to describe the results.. In our study, 6,177 CKD stage 5 patients received ESAs for ≥6 accounting quarters, of whom 64.4 % received originator ESAs, 21.1 % received biosimilars and 14.6 % received any sequence originator and biosimilar (total of 35.7 % any biosimilar). Patients receiving either originator short-acting ESAs, long-acting darbepoetin-alfa or M-PEG epoetin-beta had a median DDD consumption of 0.77, 0.81 and 0.90, respectively. Patients receiving a biosimilar short-acting ESA had a median DDD consumption of 0.82. Doses were not increased when the therapy was switched from the originator to the biosimilar ESA. These results were confirmed in 1,886 patients receiving a continuous prescription over 12 accounting quarters, with patients receiving short-acting originator ESAs, long-acting darbepoetin-alfa and biosimilar ESAs having a median daily DDD consumption of 0.80, 0.86 and 0.81, respectively.. We conclude that, based on a population based analysis, ESA consumption of patients on chronic haemodialysis is similar for biosimilar and originator ESAs.

Topics: Aged; Anemia; Biosimilar Pharmaceuticals; Cohort Studies; Databases, Factual; Drug Utilization; Erythropoietin; Female; Germany; Hematinics; Humans; Male; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Erythropoietin; Female; Humans; Male; Pilot Projects; Polyethylene Glycols; Renal Insufficiency, Chronic; Risk Factors

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Renal Insufficiency, Chronic

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Male; Peptides; Renal Dialysis; Renal Insufficiency, Chronic

In pre-clinical studies, acute erythropoietin (EPO) administration has been shown to mitigate the deleterious effects of ischemia/reperfusion injury. We reviewed our clinical experience with intraoperative EPO administration as a potential renoprotective agent during laparoscopic partial nephrectomy (LPN).. Patients who underwent LPN at our institution between August 2008 and March 2010 received 500 IU/kg EPO 30 min prior to hilar occlusion. Those who underwent LPN between August 2006 and July 2008 without receiving EPO were selected as controls. Demographic, clinical, perioperative, and estimated glomerular filtration rate (eGFR) data were compared for the cohorts preoperatively, and during short-term (<6 months) and long-term (≥6 months) follow-up.. Short-term eGFR was evaluable for 39 EPO and 29 controls, while long-term eGFR was evaluable for 26 EPO and 27 controls. Baseline demographic and clinical features of the cohorts were similar. For EPO versus controls, median short and long-term follow-up was 19 days versus 22 days and 10.2 months versus 11.9 months, respectively. Mean preoperative, postoperative, and % change in eGFR were statistically similar for the cohorts during short- and long-term follow-up, without and with adjustment for baseline renal function (unadjusted P-values = 0.28, 0.095, and 0.38, respectively, short term, and 0.61, 0.50, and 0.69, respectively, long term).. In this retrospective study, a single dose of EPO prior to hilar occlusion during LPN had no added protective impact on postoperative eGFR in the short or long term. Prospective evaluation in patients with solitary kidneys may better elucidate its potential renoprotective role in this setting.

Topics: Adult; Aged; Cohort Studies; Creatinine; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Intraoperative Period; Kidney; Laparoscopy; Male; Middle Aged; Minimally Invasive Surgical Procedures; Nephrectomy; Postoperative Period; Renal Insufficiency, Chronic; Reperfusion Injury; Retrospective Studies; Treatment Outcome; Warm Ischemia

To compare utilization and associated costs of epoetin alfa (EPO) and darbepoetin alfa (DARB), two erythropoiesis-stimulating agents (ESAs), in patients with cancer undergoing chemotherapy and patients with chronic kidney disease (CKD) not on dialysis in inpatient and outpatient hospital settings.. An analysis of medical claims recorded between January 2006 and December 2009 was conducted using the Premier Perspective Comparative Hospital database. Patients included were ≥18 years old with cancer and chemotherapy or with pre-dialysis CKD and with ≥1 claim for EPO or DARB during a hospital inpatient or outpatient treatment episode. Patients treated with both ESAs or who were receiving dialysis were excluded. Mean cumulative drug costs and dose ratios (units EPO: mcg DARB) were calculated using cumulative dose and April 2010 wholesale acquisition costs.. Cancer chemotherapy: 13,832 inpatient stays (EPO: 10,454; DARB: 3378) and 5590 outpatient treatment episodes (EPO: 2856; DARB: 2734) were identified. The inpatient and outpatient populations reported ESA dose ratios of 230:1 and 238:1 with DARB cost premiums of 42% (EPO: $948; DARB: $1348) and 38% (EPO: $3358; DARB: $4627), respectively. CKD: 148,746 hospital stays (EPO: 116,017; DARB: 32,729) and 11,012 outpatient treatment episodes (EPO: 6921; DARB 4091) were identified. The inpatient and outpatient populations reported ESA dose ratios of 251:1 and 257:1 with DARB cost premiums of 30% (EPO: $566; DARB: $738) and 27% (EPO: $2077; DARB: $2642), respectively.. The lack of randomization may have led to confounding by indication. In addition, statistical significance must be interpreted with caution in studies involving large samples.. This study of 19,422 patients with cancer receiving chemotherapy and 159,758 patients with pre-dialysis CKD reported ESA dose ratios ranging from 230:1-257:1 (units EPO: mcg DARB) and associated cost premiums of 27-42% for DARB.

Topics: Adult; Costs and Cost Analysis; Darbepoetin alfa; Databases, Factual; Epoetin Alfa; Erythropoietin; Female; Health Care Costs; Hematinics; Hospitals; Humans; Inpatients; Insurance Claim Review; Male; Middle Aged; Outpatients; Recombinant Proteins; Renal Insufficiency, Chronic; Retrospective Studies

Chronic kidney disease is a microvascular complication of diabetes mellitus (DM). Anemia is an important clinical manifestation to treat chronic kidney disease. Many subjects with poor socio-economic status having chronic kidney disease (CKD) and anaemia in a developing country can not afford the treatment with erythropoietin. This study has designed to see the efficacy of Nandrolone, a cheaper alternative; in comparison with recombinant human erythropoietin for management of anemia of pre-dialysis diabetic chronic kidney disease. Sixty adult diabetic patients with anaemia of chronic kidney disease on conservative treatment [Not on Hemodialysis (HD)] were enrolled. Patients were divided into two groups (Group 1 and Group 2) of 30 patients each. Group 1 patients received nandrolone deaconate 50 mg deep intramuscular and Group 2 recombinant human erythropoietin 100 IU per kilogram of body weight subcutaneously once weekly. Patients of both group received oral supplements in order to maintain body iron stores. All the relevant haematological and renal parameters were evaluated at the end of 3rd & 6th months. There was a statistically significant rise in haemoglobin concentration, packed cell volume, in both groups. The rise in haemoglobin concentration, in Group 2 was more marked followed by Group 1, at the end of 3rd, and 6th months. Nandrolone, though not equally effective, may be considered as a valid alternative therapy for the treatment of anemia of pre-dialysis diabetic chronic kidney disease to that of erythropoietin.

Topics: Adult; Aged; Androgens; Anemia; Cross-Sectional Studies; Erythropoietin; Female; Humans; Male; Middle Aged; Nandrolone; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Anaemia is a common finding in people with diabetes and chronic kidney disease and failure of the kidney to produce erythro-poietin in response to a falling haemoglobin concentration is a key component, correlating with the degree of albuminuria, renal dysfunction and iron deficiency. Anaemia in diabetes is associated with a number of adverse outcomes, including increased risk of all cause and cardiovascular mortality. Whether or not anaemia is a marker or mediator of adverse outcome still remains to be completely resolved. Treatment of anaemia in diabetes has quality of life benefits and reduces transfusion requirements. Correction of anaemia to normal haemoglobin concentrations is associated with significant adverse cardiovascular outcomes and is not recommended, escalating doses of erythropoiesis-stimulating agents should be avoided. The treatment of anaemia in people with diabetes and chronic kidney disease should begin with optimisation of iron stores. An aspirational haemoglobin concentration range of 10-12 g/dl with anaemia management, balances proven benefits of anaemia treatment with potential cardiovascular risk.

Topics: Anemia; Diabetes Complications; Diabetic Nephropathies; Erythropoietin; Hematinics; Humans; Iron; Iron Deficiencies; Renal Insufficiency, Chronic

Renal tissue hypoxia may play a major role in the progression of chronic renal disease. Michaely et al. used blood oxygen level-dependent magnetic resonance imaging to test this hypothesis. They found no relationship between renal oxygenation and stage of chronic kidney disease (CKD). However, renal tissue oxygenation may be related not only to the severity of renal disease but also to its underlying etiology. This added complexity confounds interpretation of data obtained from subjects with CKD due to multiple etiologies.

Topics: Animals; Erythropoietin; Female; Humans; Kidney Cortex; Kidney Function Tests; Kidney Medulla; Magnetic Resonance Imaging; Male; Oxygen; Renal Insufficiency, Chronic

To compare quality-of-care indicators for management of patients with chronic kidney disease (CKD) and type 2 diabetes among the James Bay Cree of Northern Quebec with those among residents of Montreal, Que.. A cross-sectional survey using medical records from patients seen between 2002 and 2008.. Predialysis clinics of the McGill University Health Centre in Montreal.. Thirty Cree and 51 nonaboriginal patients older than 18 years of age with type 2 diabetes mellitus and estimated glomerular filtration rates of less than 60 mL/min/1.73 m2.. Rates of anemia, iron deficiency, obesity, and renoprotective medication use among aboriginal and nonaboriginal patients.. Overall, the Cree patients were younger (59 vs 68 years of age, P < .0035) and weighed more (101 vs 77 kg,P < .001). The 2 groups were prescribed medication to control blood pressure, lipids, and phosphate levels at similar rates, but the Cree patients were more likely to receive renoprotective agents (87% vs 65%, P = .04). Despite similar rates of erythropoietin supplementation, the Cree patients were at greater risk of anemia, with an adjusted risk ratio of 2.80 (95% CI 1.01 to 7.87).. Cree patients with CKD were younger, weighed more, and were more likely to receive renoprotective agents. With the exception of the management of anemia, quality of CKD care was similar between the 2 groups.Anemia education for family physicians and continuous monitoring of quality indicators must be implemented in northern Quebec.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Health Care Surveys; Healthcare Disparities; Hematinics; Humans; Indians, North American; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Quality Indicators, Health Care; Quebec; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) are associated with serious adverse events, and maintaining hemoglobin levels within a narrow range can be difficult. We examined the quality of ESA prescribing and monitoring in pharmacist-managed ESA clinics versus usual care in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD).. Historical cohort.. Outpatients receiving ESAs for NDD-CKD at 10 Veterans Affairs Medical Centers with both pharmacist-managed ESA clinics (n = 314) and physician-based care (ie, usual care; n = 91) and 6 sites with usual care only (n = 167) on January 1, 2009, were followed up for 6 months.. Type/site of care (ie, pharmacist-managed ESA clinic, usual care at ESA clinic site, usual-care site).. Primary outcomes were proportion of hemoglobin values in the target range of 10-12 g/dL, ESA dose, and frequency of hemoglobin monitoring. Factors associated with hemoglobin values out of target range were identified using multinomial logistic regression.. More hemoglobin values were in the target range in pharmacist-managed ESA clinics (71.1% vs 56.9% for usual-care sites; P < 0.001). The average 30-day dose of darbepoetin was 163 μg in pharmacist-managed ESA clinic patients versus 240 μg in usual-care site patients and 258 μg in usual-care patients at ESA clinic sites. For epoetin, corresponding average 30-day doses were 44,890 versus 47,141 and 57,436 IU. Veterans in pharmacist-managed ESA clinics had more hemoglobin measurements on average (5.8 vs 3.6 in usual-care sites and 3.8 in usual care at ESA clinic sites; P = 0.007). In the multinomial model, usual care was associated with hemoglobin levels out of target range, whereas heart failure and diabetes were associated with values in range.. We could not assess whether different hemoglobin targets were used by usual-care providers.. Relative to usual care, pharmacist-managed clinics provided improved quality of ESA dosing and monitoring for patients with NDD-CKD.

Topics: Aged; Ambulatory Care; Ambulatory Care Facilities; Anemia; Cohort Studies; Confidence Intervals; Cross-Sectional Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hospitals, Veterans; Humans; Kidney Function Tests; Male; Middle Aged; Monitoring, Physiologic; Odds Ratio; Pharmacists; Professional Competence; Prognosis; Quality Control; Renal Insufficiency, Chronic; Risk Assessment; Severity of Illness Index; Treatment Outcome

Anemia is a major complication in patients with chronic kidney disease, as the damaged kidney is unable to produce enough erythropoietin. Peginesatide (formerly known as Hematide™) is a synthetic, peptide-based erythropoiesis-stimulating agent linked to polyethylene glycol. Based on extensive preclinical and clinical data substantiating the efficacy and safety of this agent, it was approved in the U.S. in March 2012 for the treatment of anemia due to chronic kidney disease in adult patients on dialysis. Peginesatide (Omontys®) was launched in the U.S. in April 2012.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Nephrology; Polyethylene Glycols; Renal Insufficiency, Chronic

There is a plethora of experimental data on the potential therapeutic benefits of recombinant human erythropoietin (rhEPO) and its synthetic derivatives in critical care medicine, in particular in ischemia/reperfusion injury. Most of the recent clinical trials have not shown clear benefits, and, in some patients, EPO-aggravated morbidity and mortality was even reported. Treatment with rhEPO has been successfully used in patients with anemia resulting from chronic kidney disease, but even a subset of this patient population does not adequately respond to rhEPO therapy. The following viewpoint uses rhEPO as an example to highlight the possible pitfalls in current practice using young healthy animals for the evaluation of therapies to treat patients of variable age and underlying chronic co-morbidity.

Topics: Acute Kidney Injury; Animals; Clinical Trials as Topic; Critical Illness; Drug Resistance; Erythropoietin; Humans; Models, Animal; Recombinant Proteins; Renal Insufficiency, Chronic; Reperfusion Injury

A transition in the approach to anemia management in nephrology occurred when randomized trials demonstrated that higher hemoglobin targets do not result in better outcomes and may arguably cause harm. Contradicting the speculative conclusions drawn based on earlier observational data, this has resulted in hypotheses regarding the cause of these seemingly disparate but substantively similar messages. The renal community now must struggle with how to incentivize quality care and maximize patient quality of life while minimizing the real safety signal of which we are now aware.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Labeling; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Humans; Male; Renal Insufficiency, Chronic; Stroke

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Adult; Anemia; Child; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Renal Insufficiency, Chronic; Risk; Sex Factors; Stroke

Topics: Anemia; Cerebral Hemorrhage; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Female; Hematinics; Humans; Male; Renal Insufficiency, Chronic; Stroke; Tissue Plasminogen Activator

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iron; Male; Neoplasms; Renal Insufficiency, Chronic; Stroke; Treatment Outcome

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Platelet Count; Renal Dialysis; Renal Insufficiency, Chronic; Risk; Stroke

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Evidence-Based Medicine; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic; Safety

Topics: Anemia; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

Use of erythropoiesis-stimulating agents (ESA) has been reported to increase the incidence of cardiovascular diseases at target Hb levels by more than 12.0 g/dl. The recent TREAT study found an increased incidence of stroke and cancer when maintaining the Hb level at 12.5 g/dl in diabetic patients.. Surveillance of Epoetin-Adverse Events of Stroke and Cancer (SEASCAN) was a cross-sectional study conducted under urgent conditions by the Committee on CKD Initiatives of the Japanese Society of Nephrology. Patients who were at least 18 years old and had CKD stage 4 and 5, namely, eGFR <30 ml/min/1.73 m(2), and who had visited the outpatient department of the participating facilities between December 2009 and January 2010 with at least 6 months of prior medical treatment in the participating facilities were eligible to participate in the study.. Of 7,415 patients with CKD stage 4 and 5, 3,653 (49.3%), 879 (11.9%) and 2,883 (38.9%) patients received no epoetin, epoetin for less than 6 months and epoetin for at least 6 months, respectively. In patients who did not use epoetin, use of epoetin for less than 6 months and use of epoetin for at least 6 months, the numbers of patients with stroke were 38 (1.0%), 8 (0.9%) and 27 (0.9%), respectively, and those with newly diagnosed or exacerbated malignancy were 88 (2.4%), 30 (3.4%) and 71 (2.5%), respectively, demonstrating insignificant associations between outcome and duration of treatment with epoetin (P for trend = 0.666 in stroke and 0.836 in malignancy).. No significant increase in the risk of developing symptomatic stroke and cancer was observed for the use of epoetin in current clinical practice in Japan.

Topics: Aged; Cross-Sectional Studies; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Neoplasms; Recombinant Proteins; Renal Insufficiency, Chronic; Stroke

To examine the effect of intravenous iron and erythropoietin-stimulating agents (ESAs) on glycemic control and A1C of patients with diabetes and chronic kidney disease (CKD).. This was a prospective study of patients with type 2 diabetes and CKD stage IIIB or IV undergoing intravenous iron (group A) and/or ESA (group B). Full blood profiles were determined over the study period. Glycemic control was monitored using A1C, seven-point daily glucose three times weekly, and continuous glucose monitoring (CGM).. There were 15 patients in both group A and group B. Mean A1C (95% CI) values fell in both groups (7.40% [6.60-8.19] to 6.96% [6.27-7.25], P<0.01, with intravenous iron and 7.31% [6.42-8.54] to 6.63% [6.03-7.36], P=0.013, ESA). There was no change in mean blood glucose in group A (9.55 mmol/l [8.20-10.90] vs. 9.71 mmol/l [8.29-11.13], P=0.07) and in group B (8.72 mmol/l [7.31-10.12] vs. 8.78 mmol/l [7.47-9.99], P=0.61) over the study period. Hemoglobin and hematocrit values significantly increased following both treatments. There was no linear relationship found between the change in A1C values and the rise of hemoglobin following either treatment.. Both iron and ESA cause a significant fall in A1C values without a change to glycemic control in patients with diabetes and CKD. At the present time, regular capillary glucose measurements and the concurrent use of CGM remain the best alternative measurements of glycemic control in this patient group.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Glycated Hemoglobin; Humans; Iron; Renal Insufficiency, Chronic; Treatment Outcome

Chronic kidney disease (CKD) patients develop anemia because of the low kidney erythropoietin (EPO) production, thus promoting cardiovascular complications. The degree of renal insufficiency might determine the moment to start recombinant human erythropoietin (rhEPO) therapy, but the molecular basis for these options deserves better elucidation. This study aimed to clarify the cardio-renal effects of earlier rhEPO therapy in rats with moderate chronic renal failure (CRF). Four groups of rats were evaluated for 15 weeks (control; rhEPO - 50 IU/kg/week; CRF - 3/4 nephrectomy; CRF + rhEPO) to assess renal and hematology data, EPO levels, blood pressure, heart rate, peripheral catecholamines contents, serum-transforming growth factor-β1 (TGF-β1), kidney gene expression of EPO, Caspase 9 (Casp9), and vascular endothelial growth factor (Vegf). This model of moderate CRF showed moderate and corrected anemia, hypertension, tachycardia, sympathetic overactivity, and increased serum TGF-β1 content. The remnant kidney showed a proliferative profile, with hypertrophy, downregulated gene expression of EPO, and upregulated gene expression of Vegf and Casp9. rhEPO treatment promoted erythrocytosis and prevented tachycardia and catecholamines increment, with a rise of serum TGF-β1. Furthermore, the decreased kidney gene expression of EPO and the overexpression of Casp9 were prevented, demonstrating a renoprotective action on the remnant kidney. In conclusion, rhEPO therapy promotes a protective effect on the cardio-renal axis, which might be mainly attributed to its pro-proliferative and anti-apoptotic properties. These findings might recommend its use in earlier stages of CRF, acting as an erythropoiesis stimulating agent, to efficiently correct not only the anemia, one of the major complications in these patients, but also the succeeding adverse cardio-renal effects.

Topics: Animals; Blood Pressure; Caspase 9; Disease Models, Animal; Erythropoietin; Heart Diseases; Heart Rate; Humans; Kidney; Kidney Function Tests; Male; Peripheral Nervous System; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency, Chronic; Sympathetic Nervous System; Vascular Endothelial Growth Factor A

In patients with diabetes mellitus, hemoglobin A(1c) (A1C) is commonly interpreted as a measure of long-term glycemic control, reflecting a mean glucose level over the previous 2-3 months. Although some reports suggest that treatment with recombinant erythropoietin may affect A1C values in patients undergoing hemodialysis, we know of no evidence to support this interaction in patients with chronic renal insufficiency who are not undergoing hemodialysis. In addition, we know of no evidence specific to the treatment effect of epoetin alfa and/or darbepoetin alfa on A1C. We describe a 64-year-old man with diabetes, chronic kidney disease, and anemia who was treated consecutively with epoetin alfa and darbepoetin alfa and experienced a temporal reduction in A1C level to a nadir of 4.4%. Throughout approximately 3 years of treatment with these erythropoietin analogs, the patient's total daily dose of insulin was reduced in response to his decreasing A1C values, despite elevated blood glucose levels and the absence of patient-reported hypoglycemic events. Five months after the patient's erythropoietin therapy was discontinued, his A1C value increased to 8.8%, leading us to conclude that management of the insulin dose may have been different without the falsely lowered A1C levels. Use of the Naranjo adverse drug reaction probability scale indicated a probable association between this patient's reduced A1C levels and erythropoietin therapy. This case demonstrates that both epoetin alfa and darbepoetin alfa may artificially lower A1C levels in a patient with diabetes who is not undergoing dialysis, and therefore this finding can be interpreted as a class effect. Clinicians should be aware of factors that affect A1C values, specifically erythrocyte life span. In patients receiving erythropoietin, therapeutic decisions should be based on A1C and glucose levels, as well as patient symptoms suggestive of hypo- or hyperglycemia, to avoid therapy changes that could complicate disease management.

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus; Diabetic Nephropathies; Diagnostic Errors; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Glycated Hemoglobin; Hematinics; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Anemia and hemoglobin (Hb) variability are associated with mortality in hemodialysis patients who are on erythropoiesis-stimulating agents (ESA). Our aim was to describe the degree of Hb variability present in nondialysis patients with chronic kidney disease (CKD), including those who were not receiving ESA, and to investigate the association between Hb variability and mortality.. Hb variability was determined using 6 mo of "baseline" data between January 1, 2003, and October 31, 2005. A variety of definitions for Hb variability were examined to ensure consistency and robustness.. A total of 6165 patients from 22 centers in seven countries were followed for a mean of 34.0 +/- 15.8 mo; 49% were prescribed an ESA. There was increased Hb variability with ESA use; the residual SD of Hb was 4.9 +/- 4.4 g/L in patients who were not receiving an ESA, compared with 6.8 +/- 4.8 g/L. Hb variability was associated with a small but significantly increased risk for death per g/L residual SD, irrespective of ESA use. Multivariate linear regression model explained only 11% of the total variance of Hb variability.. Hb variability is increased in patients who have CKD and are receiving ESA and is associated with an increased risk for death (even in those who are not receiving ESAs). This analysis cannot determine whether Hb variability causally affects mortality. Thus, the concept of targeting Hb variability with specific agents needs to be examined within the context of factors that affect both Hb variability and mortality.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Renal Insufficiency, Chronic; Survival Analysis

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Topics: Erythropoietin; Humans; Receptors, Erythropoietin; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Erythropoietin (EPO), traditionally known as a hematopoietic hormone, has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia and induction of neoangiogenesis. Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Anemia, CHF, and chronic kidney insuficiency often coexist and interact to cause or worsen each other in the so-called cardio-renal anemia syndrome. Treatment with EPO has shown promise in such patients. The paper reviews a case of a successful recovery of cardiac function in a patient with a severe CHF during the treatment with EPO.

Topics: Anemia; Erythropoietin; Female; Heart Failure; Humans; Middle Aged; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agent (ESA) use in the outpatient and inpatient settings through pharmacist-conducted, hospital-based chart audits is examined and discussed.. Data from four hospital chart audits conducted in 250 hospitals between October 2005 and July 2006 were pooled for analyses. Eligible hospitals were categorized by ESA sales volume, with approximately equal numbers randomly selected from each decile. The last five inpatients and outpatients within each specified month receiving either darbepoetin alfa or epoetin alfa were evaluated. Study variables by setting included ESA use, prescriber specialty, and dosage regimen.. The most common hospital locations of ESA administration were a cancer center in the outpatient setting (49%) and general medicine (57%) in the inpatient setting. ESA prescribers were most commonly hematologists and oncologists in the outpatient setting, and nephrologists were the most common prescribers in the inpatient setting. In the outpatient analysis, 2155 patients were prescribed darbepoetin alfa and 3106 were prescribed epoetin alfa. The predominant administration frequencies were every two weeks and once weekly for darbepoetin alfa, and once weekly for epoetin alfa. In the inpatient analysis, 1633 patients were prescribed darbepoetin alfa and 3231 were prescribed epoetin alfa. The predominant administration frequencies were once weekly for darbepoetin alfa and once weekly and three times weekly for epoetin alfa. Common uses for both ESAs were chemotherapy-induced anemia (outpatient setting) and anemia of end-stage renal disease with chronic dialysis (inpatient setting). There was considerable variability in ESA dosages and administration frequencies in both settings within all patient groups when analyzed by specified use.. ESA use differed between outpatient and inpatient settings in indication, frequency of administration, and specialty of the prescriber.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Drug Utilization Review; Epoetin Alfa; Erythropoietin; Hematinics; Hospital Bed Capacity, 100 to 299; Hospitals; Humans; Inpatients; Outpatients; Practice Patterns, Physicians'; Recombinant Proteins; Renal Insufficiency, Chronic; United States

It is well known that iron is pro-oxidant. Chronic kidney disease (CKD) is a pro-oxidant state, and intravenous administration of iron is frequently used to correct anemia. On one hand, there is little doubt that iron causes oxidative stress. On the other, it is far from clear whether oxidative stress, so generated, leads to poor clinical outcomes. Iron has benefits that may be independent of the correction of anemia. Furthermore, concerns surround the use of high doses of erythropoietin in causing excess heart failure and death in patients with CKD. Thus, it would be prudent if iron were to continue to be used judiciously in patients who require erythropoietin. Iron, given orally, would be the preferred first-line agent in patients not on hemodialysis. In patients with sepsis, intravenous treatment with iron should be avoided, because, in animal experiments, intravenous administration of iron can compound the inflammatory response and increase mortality. Clinical trials are needed to ascertain the risk and benefits of the intravenous administration of iron in patients with CKD.

Topics: Animals; Child; Erythropoietin; Humans; Iron; Oxidative Stress; Renal Insufficiency, Chronic; Treatment Outcome

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Frail Elderly; Hematinics; Humans; Renal Insufficiency, Chronic

Topics: Anemia; Darbepoetin alfa; Data Interpretation, Statistical; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Oxidative Stress; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Insufficiency, Chronic; Thromboembolism

Topics: Anemia; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Health Policy; Hematinics; Humans; Renal Insufficiency, Chronic; United States

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Renal Insufficiency, Chronic; Treatment Outcome; United States

To assess the effect of a disease management program in anemia of chronic kidney disease (CKD), the authors reviewedthe records of all adults treated with epoetin alfa (EPO) at their institution between September 2003 and April 2006 and compared them with a group treated through a pharmacist-managed program with patients managed by PCPs in terms of time to target hemoglobin (Hb) (11-12.9 mg/dL), percent of Hb values maintained in target range, average weekly dose of EPO, and percent of iron-saturation (T-sat) values within target range (20%-50%) over a period of six months to one year. Although pharmacist-managed patients received lower weekly EPO doses than those managed by PCPs (6,698 vs. 12,000 units, respectively; P = .0001), they achieved goal Hb faster (47.5 vs. 62.5 days, P = .11) and maintained a higher percentage of Hb and T-sat values in target range (69.8% vs. 43.9%, P = .0001, and 64.8% (vs. 40.4%, respectively; P = .043). A pharmacist-managed program may present significant clinicaland economic benefits in anemia of CKD.

Topics: Ambulatory Care; Clinical Protocols; Erythropoietin; Health Maintenance Organizations; Humans; Medical Audit; Outcome Assessment, Health Care; Pennsylvania; Pharmacists; Renal Insufficiency, Chronic; Retrospective Studies

Topics: Ambulatory Care Facilities; Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Hematocrit; Hemoglobins; Humans; Ownership; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; United States

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.

Topics: Adult; Aged; Anemia; C-Reactive Protein; Cohort Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Darbepoetin is a newer analogue of epoetin, with a longer half-life, that allows less frequent administration. There are currently no published data available for its use in infants. We report our experience with this drug in infants with chronic renal impairment, weighing less than 8 kg. Infants had baseline haemoglobin (Hb), iron, ferritin and transferrin levels measured. They were started on approximately 0.5 microg/kg per week of darbepoetin. Hb levels were checked every 2-4 weeks, and iron studies were performed every 4 weeks. Iron supplementation was prescribed to maintain ferritin levels>100 microg/l and transferrin saturation levels>20%. Follow up was for 20 weeks. Six infants with a mean weight of 4.08 kg and a mean creatinine of 259 micromol/l were included. Three infants were medically stable throughout the study, and the mean darbepoetin dose was decreased to 0.25 microg/kg per week. Their dosing interval was increased to every 3-4 weeks. The other three infants were less stable and had multiple medical problems, including periods of haemodialysis and surgery. These infants failed to reach target Hb level, despite an increase in the mean dose of darbepoetin to 1.2 microg/kg per week. In conclusion, darbepoetin can be successfully administered to infants with chronic renal insufficiency, but the dose needs to be tailored to each individual. Administration would be facilitated by smaller unidose syringes.

Topics: Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Infant; Iron; Male; Renal Insufficiency, Chronic; Retrospective Studies; Transferrin; Treatment Outcome

Anemia of renal failure is primarily a problem of decreased RBC production due to erythropoietin deficiency. RBC survival is also reduced, perhaps due to decreased RBC deformability. This study measured blood viscosity over a range of shear rates in erythropoietin-treated patients on hemodialysis (HD), and compared the findings to matched patients with chronic renal insufficiency (CRI) and healthy controls.. Four groups (control, CRI, non-diabetic HD, and diabetic HD) of 9 matched subjects were recruited. Blood viscosity was measured using a cone-plate viscometer over a variety of shear rates (11 to 225 s(-1)).. Control subjects had lower viscosity values throughout all shear rates when compared to the 3 renal disease groups (P value=0.039). A trend was observed to higher levels of renal function being associated with decreased blood viscosity in patients with CRI.. Patients with kidney disease have increased blood viscosity at all shear rates. This may be related to changes in RBC shape and decreased deformability in patients with kidney disease, independent of HD- or DM-status. This may have implications for strategies to treat anemia in these patients.

Topics: Aged; Analysis of Variance; Blood Viscosity; Case-Control Studies; Diabetic Nephropathies; Erythrocyte Aging; Erythrocyte Deformability; Erythrocytes; Erythropoietin; Female; Hemorheology; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Erythropoietin; Humans; Kidney Transplantation; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Adult; Androgens; Anemia; Ascorbic Acid; Blood Cell Count; Blood Transfusion; Carnitine; Contraindications; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Male; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Vitamins

Topics: Adolescent; Androgens; Anemia; Ascorbic Acid; Blood Cell Count; Blood Transfusion; Carnitine; Child; Child, Preschool; Contraindications; Erythropoietin; Ferritins; Hemoglobins; Humans; Infant; Infant, Newborn; Iron; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Vitamins

To determine patient preference for once-weekly Epoetin alfa versus once-monthly (QM) darbepoetin alfa in patients with chronic kidney disease (CKD) not receiving dialysis.. AMPS (Aranesp Monthly Preference Study) consisted of two studies of similar design, each with a 2-week screening/baseline period, a 20-week QM darbepoetin alfa dosing period, and an 8-week follow-up period. Patients aged > or = 18 years had a nephrologist-reported diagnosis of CKD but were not receiving dialysis, and were required to have at least two hemoglobin levels within 10-12 g/dL and to have been receiving a stable dose (< 25% change) of once-weekly or once-every-other-weekly Epoetin alfa for at least 8 weeks. At week 21, patients could continue on QM darbepoetin alfa or revert back to their previous Epoetin alfa regimen. The primary analysis assessed patient preference at week 21 for QM darbepoetin alfa versus previous once-weekly Epoetin alfa.. AMPS enrolled 442 patients: 54% were female, 67% were Caucasian, and mean (SD) age was 68.3 (13.5) years. At week 21, 346 patients remained on study. Of the patients converted from once-weekly Epoetin alfa, 86% (138/161) preferred darbepoetin alfa QM, and of all patients who expressed a preference, regardless of previous Epoetin alfa dosing frequency, 96% (305/319) preferred QM darbepoetin alfa. Mean (SD) hemoglobin at week 29 of the study was similar to mean hemoglobin at baseline (for those who completed the study and were receiving QM darbepoetin alfa at week 29: 11.2 [1.1] g/dL at week 29 versus 11.4 [0.7] g/dL at baseline). QM darbepoetin alfa was well tolerated.. These data show that the majority of study patients preferred QM darbepoetin alfa to more frequent Epoetin alfa, and that QM darbepoetin alfa maintained hemoglobin levels at week 29 and was well tolerated over the study period. The single-item questionnaire could be a potential limitation of this study and further investigation with a multi-question instrument may be helpful in confirming these results.

Topics: Aged; Anemia; Clinical Trials as Topic; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Patient Satisfaction; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia, Iron-Deficiency; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Infusions, Intravenous; Iron Compounds; Practice Guidelines as Topic; Quality of Health Care; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome