Roxadustat in the treatment of anaemia in chronic kidney disease

Introduction: 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.     

Hepcidin as a therapeutic target for anemia and inflammation associated with chronic kidney disease

Introduction: Anemia is a common manifestation of chronic kidney disease (CKD). The pathogenesis of CKD-associated anemia is multifactorial. Our understanding of the molecular control of iron metabolism has improved dramatically because of the discovery of hepcidin and attempts to introduce new drugs to stimulate erythropoiesis or affect the hepcidin-ferroportin pathway have recently emerged.

Areas covered: We examine the possible role of hepcidin in iron metabolism and regulation and the potential therapeutic options involving hepcidin and hepcidin-ferroportin axis in renal anemia treatment. We focus on therapeutic targeting of hepcidin, the hepcidin-ferroportin axis and key molecules such as anti-hepcidin antibodies, spigelmers, and anticalins. We also discuss compounds affecting the bone morphogenetic protein receptor [BMP/BMPR] complex and molecules that influence hepcidin, such as hypoxia-inducible factor 1 stabilizers.

Expert opinion: Hepcidin is a key regulator of iron availability and is a potential future therapeutic target for managing anemia that is associated with CKD. There are potential risks and benefits associated with novel sophisticated therapies and there are several novel options on the horizon; however, clinical data are currently limited and need development. Inhibition of hepcidin via various pathways might be a viable adjunctive therapeutic option in other clinical situations.     

Emerging drugs for the treatment of kidney disease-induced anemia

Introduction: Anemia has been remained one of the most characteristic and visible manifestations of chronic renal failure. Correction of anemia requires two main treatment strategies: increased stimulation of erythropoiesis, and maintenance of an adequate iron supply to the bone marrow.

Areas covered: Erythropoiesis activating agents became a mainstay in the treatment of renal anemia for more than 25 years. Recently, there have been several attempts to introduce new drugs to stimulate erythropoiesis or affect the hepcidin-ferroportin pathway. Orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives. They not only increase hemoglobin, but also suppress hepcidin production and improve iron availability. Novel iron preparations, may also help to ameliorate anemia, with acceptable safety profile and other beneficial properties such a phosphate binding.

Expert opinion: One should be aware of potential risks and benefits of novel sophisticated therapies and their role in the management of renal anemia remain to be established. In particular HIF stabilizers needs to be proven safe, or even safer than ESAs, in large long-term safety studies testing hard end points, due its ubiquitous nature and the regulation of variety of biological processes potentially leading to unexpected side effects. Besides safety, cost-effectiveness appears the major issue in the modern world, including nephrology.     

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.     

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.     

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.     

高尿酸血症对未透析慢性肾脏病残余肾功能的影响及非布司他的保护效果分析

目的 分析高尿酸血症(HUA)对未透析慢性肾脏病(CKD)病人残余肾功能的影响及非布司他的保护效果.方法 回顾性纳入2017年8月至2018年8月于滁州市第一人民医院肾病科住院的未透析CKD病人188例,其中合并HUA者86例,无HUA者102例.对合并HUA者的86例根据治疗方法不同分为非布司他组(46例)和别嘌醇组...     

Managing chronic kidney disease in diabetes patients with the latest chemical therapies

Introduction: During the years, while treatment strategy for diabetes mellitus has improved, the incidence of diabetes worldwide increases continuously. Chronic kidney disease (CKD) is one of the major diabetic microvascular complications, and a primary cause leading to end-stage renal disease (ESRD). The progression to ESRD, affected by hyperglycemia and hypertension, is characterized by microalbuminuria and macroalbuminuria. With advances in understanding the pathogenesis of CKD in diabetic patients, many novel therapeutic targets have been proposed, and the corresponding agents are being developed continually to prevent the progression of CKD.

Areas covered: This review focuses on those tested in phase III clinical trials for the treatment of CKD in diabetic patients, including renin-angiotensin system blockers, aldosterone antagonists, calcium channel blockers, TGF-β inhibitors, protein kinase C inhibitors, advanced glycation end products inhibitors, GLP-1 analogues, DPP-4 inhibitors, SGLT2 inhibitors, endothelin receptor antagonists, and so on.

Expert commentary: The ideal control of glucose and blood pressure and healthy lifestyle are prerequisite for diabetic patients, despite the progression of CKD is inevitable. Over the last few years, several agents have been developed to delay and even reverse progression of CKD in diabetic patients.     

Hippo signaling in acute kidney injury to chronic kidney disease transition: Current understandings and future targets

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Current and future therapies for treating chronic spontaneous urticaria

Introduction: Chronic spontaneous urticaria (CSU) is a disabling condition that causes deterioration of quality of life.

Areas covered: The international EAACI/GA²LEN/EDF/WAO guidelines have provided a stepwise treatment algorithm for CSU management. Second-generation H₁-antihistamines are the first-line treatment, and the second step is the up-dosing of the same drugs. In refractory patients, the guidelines recommend the addition of omalizumab, ciclosporin A or montelukast. Systemic corticosteroids can be used as a short course during acute exacerbations. A plethora of alternative treatments has been evaluated, although the overall level of evidence for such treatments is low. Future treatment options may include inhibitors of skin mast cells and antagonists to mast cell-activating signals that are relevant for the induction of CSU signs and symptoms.

Expert opinion: The only licensed options included in the guidelines algorithm are standard-dosed second-generation H₁-antihistamines and omalizumab. High-quality evidence has documented a rapid and strong symptomatic effect of omalizumab in CSU, although the optimal long-term regimens should be further investigated. The role of alternative drugs deserves additional studies. The potential of the existing treatments for inducing remission of CSU is unknown, and this is an important area of research, as is the evaluation of predictors of response, prognostic factors, and pathomechanisms.     

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.     

Measurement of renal function in patients with chronic kidney disease

Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.     

中医在儿童慢性肾脏病治疗中的作用初探

论述了中医在儿童慢性肾脏病治疗中的作用。针对儿童慢性肾脏病症状特点,以西医诊断分5期进行不同阶段的辨证施治。对于疾病发生中的常见并发症提出可行的中医治疗方法。发挥中医标本兼治之特色,延缓疾病进展,为儿童慢性肾脏病治疗提供新思路。     

Emerging drugs for chronic kidney disease

Introduction: Chronic kidney disease (CKD) is a worldwide health problem. Despite remarkable headway in slowing the progression of kidney diseases, the incidence of end-stage renal disease (ESRD) is increasing in all countries with a severe impact on patients and society. The high incidence of diabetes and hypertension, along with the aging population, may partially explain this growth. Currently, the mainstay of pharmacological treatment for CKD, aiming to slow progression to ESRD are ACE inhibitors and angiotensin II receptor blockers for their hemodynamic/antihypertensive and anti-inflammatory/antifibrotic action. However, novel drugs would be highly desirable to effectively slow the progressive renal function loss.

Areas covered: Through the search engines, PubMed and ClinicalTrial.gov, the scientific literature was reviewed in search of emerging drugs in Phase II or III trials, which appear to be the most promising for CKD treatment.

Expert opinion: The great expectations for new drugs for the management of CKD over the last decade have unfortunately not been met. Encouraging results from preliminary studies with specific agents need to be tempered with caution, given the absence of consistent and adequate data. To date, several agents that showed great promise in animal studies have been less effective in humans.     

非布司他治疗慢性肾病伴高尿酸血症的疗效及机制分析

目的 探究非布司他治疗慢性肾病伴高尿酸血症的疗效及机制.方法 从2019年3月～2020年3月收治的慢性肾病伴高尿酸血症患者中选取82例作为研究对象,将其随机分为对照组与观察组,各41例.对照组予以别嘌醇治疗,观察组在对照组基础上予以非布司他治疗,比较两组患者的治疗疗效、血清生化指标变化及药物不良反应.结果 观察组患者...     

Effect of renal function and hemodialysis on the serum tumor markers in patients with chronic kidney disease

In patients with chronic renal failure, whether they have had hemodialysis or not, the specificity of some of the serum tumor markers for the diagnosis of the corresponding tumors is decreased while others remain as valuable as they are in patients with normal kidney function. The detection of tumor markers is extensively used for the diagnosis of corresponding tumors. It has been recently shown that some tumor markers are higher in patients with chronic kidney disease (CKD) than in the normal population. The effects of renal function and hemodialysis were examined on serum levels of some of the tumor markers including CEA, CA₁₉₉, CA₁₂₅, AFP, CA₁₅₃, CA₇₂₄, CYFRA_21-1, NSE, SCC-Ag, PSA, and fPSA. The 232 non-dialysis patients with CKD and 37 chronic uremic patients treated with maintenance hemodialysis were enrolled in this study. The 232 non-dialysis patients were divided into three groups according to their Ccr. In group 1, Ccr was ⩽ 25 mL/min. In group 2, Ccr was between 25 and 50 mL/min. In group 3, Ccr was ⩾ 50 mL/min. The male patients were also divided into three groups to compare the serum levels of PSA and fPSA among the three groups. Nine tumor markers in 37 uremic patients were tested. For comparison, 37 non-dialysis patients with similar Ccr of the same age and gender served as controls. There existed significant differences in serum levels of CEA, CA₁₉₉, CYFRA_21-1, NSE, and SCC-Ag among different Ccr groups and the markers bore a negative correlation with Ccr. There were no significant differences among the three groups in the serum concentrations of CA₁₂₅, AFP, CA₁₅₃, CA₇₂₄, PSA and fPSA. The serum levels of CA₁₂₅ and NSE were significantly higher (P < 0.01) in hemodialysis patients than in the nondialysis control patients. In patients with chronic renal failure, who were or were not on hemodialysis, the specificity of serum CEA, CA₁₉₉, CYFRA_21-1, NSE, CA₁₂₅ and SCC-Ag for the diagnosis of the corresponding tumors was decreased while serum AFP, CA₁₅₃, CA₇₂₄, PSA and fPSA were as valuable as they were in patients with normal kidney function. Hemodialysis further increased the serum level of CA₁₂₅ and NSE. Translated from Shanghai Medical Journal, 2007, 30(2): 81–85 [译自: 上海医学]     

Special considerations for the treatment of chronic kidney disease in the elderly

Chronic kidney disease (CKD) is common in older adults, and its burden is expected to increase in older populations. Even if the knowledge on the approach to older patient with CKD is still evolving, current guidelines for pharmacological management of CKD does not include specific recommendations for older patients. Additionally, decision-making on renal replacement therapy (RRT) for older patients is far from being evidence-based, and despite the improvement in dialysis outcomes, RRT may cause more harm than benefit compared with conservative care when prognostic stratification is not carefully assessed. The use of comprehensive geriatric assessment tools could help clinicians in applying a more informed decision-making. Finally, physical exercise and rehabilitation interventions also represents a promising therapeutic strategy.     

Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia

Importance of the field: Anemia caused by chronic kidney disease and other chronic diseases or conditions can be managed by the treatment of biologic-based erythropoiesis stimulating agents (ESAs). Although these ESAs are successful in treating these anemic conditions, a small molecule-based anti-anemia medicine can potentially revolutionize the treatment of anemia by bringing convenience to patients and being cost effective. Prolyl hydroxylase domain-containing protein (PHD) inhibitors may provide an opportunity for the development of small molecule anti-anemia medicines.

Areas covered in this review: This review covers efforts to target PHD enzymes for stabilization of hypoxia-inducible factor (HIF)-α subunits under normal oxygen levels as an attractive strategy to upregulate the expression of erythropoietin and genes involved in iron metabolism for the treatment of anemia.

What the reader will gain: The reader will gain a brief summary of recent advances in HIF and PHD biology and a review of patents/patent applications on the subject of PHD inhibitors as HIF stabilizers for the treatment of anemia.

Take home message: Several classes of PHD enzyme inhibitors have been disclosed and several are currently in clinical trials for the development of small molecule-based therapeutics for the treatment of anemia.     

芜湖市健康体检人群慢性肾脏疾病患病率及相关危险因素调查

目的： 调查芜湖市健康体检人群慢性肾脏病（CKD）患病率以及以及与CKD相关独立危险因素。方法： 40377名芜湖市健康体检居民（男性24164名、女性16213名）入选横断面研究。测量体重、身高和血压,同时检测血常规、尿常规,血脂和肾功能,计算GFR（eGFR）。eGFR＜ 60 ml/min/1.73 m2,和/或蛋白尿、血尿者被定义为CKD。 结果： 芜湖市健康体检人群CKD流行率为6.3%,男性高于女性（7.1% vs 5.0%）。蛋白尿、血尿及eGFR＜ 60 ml/min/1.73 m2 患病率分别为1.7%、2.2%、2.9%,并随着年龄的增长而增长。经年龄、性别校正后,多因素回归分析显示高尿酸血症、糖尿病、贫血、年龄及高血压为CKD相关独立危险因素（优势比（OR）： 2.28, 1.70, 1.65, 1.48, 和 1.29）。结论： 芜湖市城区人口CKD患病率低于国内其他研究报道,芜湖市人群CKD早期防治中要注意上述危险因素。