Emerging drugs for treatment of anemia of chronic kidney disease

Introduction: 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.

Areas covered: 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.

Expert opinion: Anemia associated with CKD is an important area for development of newer therapies which are potentially safer and more convenient to administer.     

Erythropoiesis‐stimulating agents: development,detection and dangers

Epoetin alfa, the first member of the family of erythropoiesis stimulating agents (ESAs), was introduced to the market in 1989. Since then development has progressed to epoetins of the third generation. Currently drugs that use alternative approaches to stimulate erythropoiesis are under development. Uptake of all available ESAs into doping has occurred rapidly after their introduction. A multitude of dangers to health are associated with the illicit use of these substances. Different approaches to detect ESAs in doping control have been developed to comply with the very diverse nature of the compounds used. Future developments in the field of ESA require the development of new techniques in doping analysis. This review gives an overview of the development of ESA and its detection methods as well as future developments. [Correction made here after initial online publication] Copyright © 2009 John Wiley & Sons, Ltd.     

Safety issues related to erythropoiesis-stimulating agents used to treat anemia in patients with chronic kidney disease

Introduction: Erythropoiesis-stimulating agents (ESAs) have been the main therapy for anemia in CKD patients since the late eighties. Since then, treatment indications have progressively changed, together with a progressive increase in therapeutic targets, in terms of hemoglobin levels.

Areas covered: This paper discusses possible concerns about ESA use and increased cardiovascular risk (in particular stroke), hypertension, cancer progression and the development of pure red cell aplasia. A literature search was done on PubMed to obtain studies about the adverse effects of ESA in the CKD population.

Expert opinion: The publication of the TREAT study has largely contributed to the concerns about ESA use, indicating that complete anemia correction may not be safe in the CKD population. This may be particularly true in high-risk patients, especially if hyporesponsive to ESA treatment. However, there is a gray area of no evidence either way for intermediate levels (11.5 – 13 g/dl), in comparison with higher or lower levels. New recommendations about ESA use in the CKD population by the Food and Drug Administration seem to move toward treatment individualization.     

A simple method to immunopurify erythropoiesis stimulating agents from urine,aiming to optimize erythropoietin screening by SAR‐PAGE

The efficiency of the immunopurification step of urinary erythropoietin (EPO) and recombinant forms is important for their optimal detection in antidoping screening. Previous investigations of immunopurification techniques have been done for immunomagnetic beads, EPO Purification Kit (EPK) columns (MAIIA Diagnostics), and enzyme‐linked immunosorbent assay (ELISA) microplates (Stemcell Technologies) conjugated/coated with anti‐EPO antibodies. In this study, a new immunopurification technique using anti‐EPO sepharose gel beads, developed by MAIIA Diagnostics, to simplify and minimize sample handling was evaluated. This EPO Purification Gel Kit (EPGK) was compared with our current routine EPK for limit of detection (LOD). Linearity, recovery, repeatability, sample incubation time, and sample volume were also evaluated for EPGK. The LODs and linearity for EPK and EPGK were comparable to each other and the recovery for BRP, NESP, CERA, and EPO‐Fc were within the range of other studies, and concentration of the sample eluate improved the recovery results. Little variation was seen within days, between days, and between operators. A 90 minute incubation of the sample with the sepharose gel beads is sufficient for most of the erythropoiesis stimulating agents (ESAs) tested, with 10 mL being an optimal sample volume for EPGK. The improved sample handling, higher sample throughput and the reduced working time demonstrate that the EPGK is a better alternative to the current MAIIA EPK immunopurification method for urine. The EPO Purification Gel Kit (from MAIIA Diagnostics) was evaluated and validated for immunopurification of endogenous erythropoietin and exogenous erythropoiesis stimulating agents from urine samples. The kit was a better alternative to that currently used (EPO Purification Kit) in many antidoping laboratories because it improves sample handling and increases sample throughput.     

Evaluation of anemia management by algorithms in patients with chronic kidney disease who are not receiving dialysis

Background:

Anemia commonly develops in patients with chronic kidney disease and is strongly associated with adverse clinical outcomes. There are currently no published studies evaluating the efficacy of a nurse-driven anemia-management protocol for patients with chronic kidney disease who are not receiving dialysis.

Objectives:

To evaluate the efficacy of an anemia-management protocol in terms of achieving hemoglobin and transferrin saturation levels within the target range, as well as associated utilization of medications, relative to individualized dosing of medications by nephrologists.

Methods:

An algorithm for nurse-driven management of anemia was introduced in April 2009 at a kidney function clinic in a large urban centre. The charts of patients with chronic kidney disease who were not undergoing dialysis were reviewed before (July to December 2007) and after (July to December 2009) implementation of the protocol. Patients’ data for hemoglobin, transferrin saturation, and doses of iron and erythropoiesis-stimulating agents were collected for each of the 6-month study periods.

Results:

In total, 390 patients were treated for anemia before and 434 patients after introduction of the protocol. The anemia-management protocol was non-inferior to individualized dosing for maintenance of hemoglobin levels within the target range of 110–120 g/L: percentage of measured levels within target range 33.3% (485/1456) before versus 34.2% (504/1472) after (absolute difference 0.9 percentage points, 95% confidence interval [CI] −2.5 to 4.4). The criteria for non-inferiority were not met for maintenance of transferrin saturation within the target range of 22%–50%: percentage of levels within target range 58.8% (374/636) before versus 56.9% (403/708) after (absolute difference 1.9 percentage points, 95% CI −3.4 to 7.2). There were no statistically significant differences in mean doses of epoetin alfa, darbepoetin, or iron before and after introduction of the protocol. Similarly, there were no statistically significant differences in number of dose changes for epoetin alfa, darbepoetin, or iron.

Conclusion:

The nurse-driven anemia-management protocol was non-inferior to dosing by nephrologists in terms of managing hemoglobin levels. It would be reasonable to use an anemia-management protocol for patients with chronic kidney disease who are not receiving dialysis.     

国产与进口重组人红细胞生成素治疗血透病人贫血的比较

目的：研究国产重组人红细胞生成素（ｒｈ Ｅ Ｐ Ｏ） 对慢性肾功能衰竭伴肾性贫血的临床疗效。方法：将６８ 例慢性肾功能衰竭伴肾性贫血的血液透析（ 血透） 病人随机分成国产ｒｈ Ｅ Ｐ Ｏ 组３８ 例（ 男性２２例,女性１６ 例;年龄４５ ａ ±ｓ ４ ａ） 予国产ｒｈ Ｅ Ｐ Ｏ ８０～１６０ Ｕ／ｋｇ ,ｉｖ , 进口ｒｈ Ｅ Ｐ Ｏ 组３０ 例（ 男性１８ 例,女性１２ 例;年龄４１ ａ ±３ ａ） 予进口ｒｈ Ｅ Ｐ Ｏ ３０ ～８０ Ｕ／ｋｇ ,ｉｖ , 均为每周２ ～３ 次,连续用药治疗２４ ｗｋ ,观察血红蛋白（ Ｈｂ） 、血细胞比容（ Ｈｃｔ） 、血清铁和血清铁蛋白的动态变化。结果：国产ｒｈ Ｅ Ｐ Ｏ 组总有效率为９５ ％ 。进口ｒｈ Ｅ Ｐ Ｏ 组总有效率为１００ ％ （ Ｐ＞０ ．０５） ,２ 组各有２ 例因出现血压升高而被迫停药。结论：国产ｒｈ Ｅ Ｐ Ｏ（８０ ～１６０ Ｕ／ｋｇ） 的疗效基本上与进口ｒｈ Ｅ Ｐ Ｏ 组（３０ ～８０ Ｕ／ｋｇ） 一致。     

Current and future chemical therapies for treating anaemia in chronic kidney disease

Introduction: Erythropoiesis-stimulating agents (ESAs) are not perfect, since they have potential side effects. Iron therapy is also receiving growing attention in recent years.

Areas covered: We performed a literature search on PubMed using the following key words: anemia, chronic kidney disease, HIF stabilisers, sotatercept, actin traps, iron, iron-containing phosphate binders, iron dialysate. We reviewed new drugs that are under clinical development to obtain better safety and activity and/or easier and cheaper manufacturing processes in comparison to available ESAs. We also considered new strategies to increase iron stores.

Several phase 1 and 2 studies support the beneficial role of increasing Hypoxia Inducible factor (HIF) activity for stimulating endogenous erythropoiesis. Sotatercept and luspatercept, two activin traps, are undergoing clinical development mainly for indications other than CKD. They have the additional effect of improving osteoporosis. Iron-containing phosphate binders have become available recently.

Expert opinion: Several medical needs are unmet with ESA. HIF stabilisers are the most appealing drugs undergoing clinical development. They expose patients to lower levels of EPO than ESA, possibly reducing unintended effects. Their long-term safety is still to be demonstrated. One new iron-containing phosphate binders has the potential of combining two indications: hyperphosphoremia and iron deficiency, possibly improving compliance.     

Pharmacotherapy of kidney stones

Background: Since their inception nearly two decades ago, erythropoietin-stimulating agents (ESAs) have revolutionized the care of patients with renal anemia. Until recently, treatment options included the epoetins and darbepoetin alfa. As the use of these agents for chronic kidney disease (CKD) became widespread, the introduction of ESAs – touted for their longer-acting properties – was excitedly anticipated. Objectives: To review the option of methoxy polyethylene glycol-epoetin beta for ESA therapy in patients with renal anemia. Methods: Peer-reviewed scientific literature, published abstracts and renal business journals were reviewed in the writing of this opinion. Results/conclusion: Methoxy polyethylene glycol-epoetin beta (CERA) is an effective long-acting ESA approved for treatment of renal anemia and available for use outside of the United States. CERA corrects and maintains hemoglobin (Hb) levels in patients with CKD and its efficacy mirrors that of the epoetins and darbepoetin alfa. CERA holds promise for its safety record, administration requirements, and the potential impact on social and pharmacoeconomic barriers to treatment for patients with renal anemia.     

促红细胞生成素治疗慢性心衰合并贫血的临床观察

目的:观察在慢性充血性心力衰竭合并贫血时标准治疗基础上加用促红细胞生成素(EPO)的临床疗效。方法:入选的57例伴有贫血的慢性充血性心力衰竭患者随机分为治疗组(30例)和对照组(27例)。对照组给予心衰的标准治疗,治疗组给予标准治疗同时给予EPO和铁剂,观察并比较两组治疗6个月前后Hb、心功能分级、LVEF及BNP。结果:治疗组Hb、心功能分级和LVEF较治疗前有显著改善(P<0.05);两组治疗后血浆BNP水平均下降,两组治疗后血浆BNP比较有差异(P<0.05)。结论:EPO治疗慢性充血性心力衰竭合并贫血患者有效,能改善心功能指标。     

罗沙司他治疗肾性贫血效果的影响因素分析

目的:探讨使用罗沙司他治疗肾性贫血患者后所取得效果的影响因素.方法:选取广州医科大学附属第二医院2019年1月1日至2020年12月31日诊断为肾性贫血且使用罗沙司他治疗的182例患者数据资料,进行回顾性分析.依据患者的治疗效果分为治疗有效组121例,治疗无效组61例.对比2组的调查结果数据,分析肾性贫血患者治疗效果的...     

Peginesatide as a new approach for treating anemia of CKD patient: is it like a falling star?

Any scientific innovation needs to translate into a significant benefit. Peginesatide is noninferior to other erythropoiesis stimulating agents (ESAs) in terms of efficacy, and it shares the advantages of other long-acting ESAs: delayed administration frequency and no changes in dose needs according to the administration route. The molecular structure of peginesatide does not require the use of recombinant DNA technology during the manufacturing process, making its synthesis simpler and likely economically cheaper. During clinical development, its safety profile seemed to be safe, excepting the potential increase in the risk of safety end-point events in nondialysis CKD patients. However postmarketing serious hypersensitivity reactions have completely changed the scenario and urgently needs in-depth clarification. This promising drug seems to have prematurely finished its prospects.     

Dual Therapeutic Effects of an Albumin-Based Nitric Oxide Donor on 2 Experimental Models of Chronic Kidney Disease

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.     

治疗肾性贫血新药罗沙司他

慢性肾脏病（CKD）会导致肾性贫血,严重的肾性贫血会增加患者的死亡率。2017年10月18日FibroGen公司宣布国家食品药品监督管理总局（CFDA）已受理其提交的口服新药罗沙司他（Roxadustat,FG-4592）的上市申请,如获批准,将成为全球第一个低氧诱导因子（HIF）脯氨酰羟化酶（PH）抑制剂类的首创新药,中国将成为最先批准的国家。罗沙司他是一种新型HIF-PH酶抑制剂,通过稳定HIF,抑制其降解,从而激活相关基因的转录,产生相应的生理反应,发挥抗肾性贫血的作用,而且疗效显著,不良反应少,给药方便,可减少或规避铁剂的使用。介绍罗沙司他的作用机制、药动学、临床研究、不良反应等研究进展,为临床应用提供参考。     

国产重组人红细胞生成素治疗肾性贫血的疗效和安全性

目的比较国产与进口注射用重组人红细胞生成素(rhEPO)治疗肾性贫血的疗效及其安全性。方法采用前瞻性、随机、对照、多中心研究方法,选取肾性贫血患者134例,随机分为2组。试验组和对照组分别给予国产或进口(rhEPO)治疗,初始剂量为6 000 U.wk-1(100~150 U.kg-1.wk-1),分2次皮下注射。治疗前后监测Hb、HCT、肝肾功能、血电解质等水平的变化。结果共完成130例,退出4例。治疗结束时,试验组与对照组有效率分别为93.8%(61/65)与89.2%(58/65),P>0.05。国产rhEPO主要不良反应为高血压和注射部位疼痛,但均能耐受,无需停药。结论国产rhEPO治疗肾性贫血疗效显著、安全性高,与进口同类产品相似。     

Darbepoetin alfa for anemia in chronic kidney disease

Anemia of chronic kidney disease (CKD) is common, yet it is often under-recognized and undertreated, with serious adverse consequences. It is highly responsive to treatment with erythropoiesis-stimulating agents (ESAs). Darbepoetin alfa is a hyperglycosylated ESA that has a lower affinity to the erythropoietin receptor but a longer half-life than recombinant human erythropoietin, irrespective of administration by a subcutaneous or intravenous route. Owing to its pharmacokinetic characteristics, darbepoetin alfa has been used in extended dosing intervals ranging from once every week to once every 4 weeks in CKD patients on dialysis, as well as in CKD patients not on dialysis. Darbepoetin alfa has been shown to be safe and effective in clinical trials. The safety profile of darbepoetin alfa is similar to that of recombinant human erythropoietin. While target hemoglobin levels in CKD anemia remain debatable, treatment of anemia with ESAs has the proven benefits of reducing transfusions and improving quality of life. Darbepoetin alfa has the potential to simplify the treatment of CKD anemia with many advantages, including infrequent dosing, improved patient convenience and compliance, and decreased healthcare resource utilization.     

New alternatives for erythropoietin therapy in chronic renal failure

Erythropoietin (EPO) is one of the main cytokines involved in the regulation of erythropoiesis. The main site of EPO production are the kidneys. An altered EPO production leads to pathological conditions such as anemia and polycythaemia. Due to the progressive loss of renal peritubular cells, patients with chronic kidney disease (CKD) have low EPO plasma levels. This decreases erythron stimulation with the direct consequence of developing anemia. Before the introduction in the clinical practice of rHuEpo, in the late 1980s, the only solution for treating this type of anemia were blood transfusions and anabolic steroids. Even rHuEpo has proven to be safe and effective for treatment of anemias, there are some concerns about its cost, the need for frequent parenteral administration, and development of anti-EPO antibodies. These inconveniences prompted the search for novel erythropoiesis stimulating agents. Different strategies lead to isolation or chemical synthesis of such agents as darbepoetin alfa and EPO mimetics. In this review, we present some general aspects of EPO biology, with emphasis on chronic renal failure, and expose some of the alternatives to EPO used for anemia correction.     

国产促红细胞生成素治疗肾性贫血疗效观察

目的：观察国产重组人促红细胞生成素(rHuEPO)治疗肾性贫血的疗效。方法：选择24例血透慢性肾衰贫血病人，全部使用rHuEPO，每周150IU／kg，分3次皮下注射。观察用药12周后血生化的变化。结果：经治疗15例显效，7例进步，1例无效，总有效率为95．8％。病人血红蛋白、红细胞计数、红细胞压积和网织红细胞均显著增加，生活质量得到改善。结论：国产的促红细胞生成素能安全、有效地改善血透慢性肾衰病人贫血状态。     

Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease

Background: Iron deficiency anemia (IDA) is a common problem in patients with chronic kidney disease (CKD). Use of intravenous (i.v.) iron effectively treats the resultant anemia, but available iron products have side effects or dosing regimens that limit safety and convenience. Objective: Ferumoxytol (Feraheme^?) is a new i.v. iron product recently approved for use in treatment of IDA in CKD patients. This article reviews the structure, pharmacokinetics, and clinical trial results on ferumoxytol. The author also offers his opinions on the role of this product in clinical practice. Methods: This review encompasses important information contained in clinical and preclinical studies of ferumoxytol and is supplemented with information from the US Food and Drug Administration. Results/conclusion: Ferumoxytol offers substantial safety and superior efficacy compared with oral iron therapy. As ferumoxytol can be administered as 510 mg in < 1 min, it is substantially more convenient than other iron products in nondialysis patients. Although further experience with this product is needed in patients at higher risk of drug reactions, ferumoxytol is likely to be highly useful in the hospital and outpatient settings for treatment of IDA.