Bruce Gordon, Schulga Peter, Reynolds Ben C
Royal Hospital for Children Glasgow, Paediatric Nephrology, Glasgow, UK.
Clin Kidney J. 2022 Feb 26;15(8):1483-1505. doi: 10.1093/ckj/sfac058. eCollection 2022 Aug.
Erythropoiesis-stimulating agents (ESAs) revolutionized the management of anaemia in chronic kidney disease (CKD) when introduced in the late 1980s. A range of ESA types, preparations and administration modalities now exist, with newer agents requiring less frequent administration. Although systematic reviews and meta-analyses have been published in adults, no systematic review has been conducted investigating ESAs in children.
The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for the conduct of systematic reviews was used. All available literature on outcomes relating to ESAs in children with CKD was sought. A search of the MEDLINE, CINAHL and Embase databases was conducted by two independent reviewers. Inclusion criteria were published trials in English, children with chronic and end-stage kidney disease and use of any ESA studied against any outcome measure. An assessment of risk of bias was carried out in all included randomized trials using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Two tables were used for data extraction for randomized and observational studies. Study type, participants, inclusion criteria, case characteristics, follow-up duration, ESA type and dosage, interventions and outcomes were extracted by one author.
Of 965 identified articles, 58 were included covering 54 cohorts. Six were randomized trials and 48 were observational studies. A total of 38 studies assessed the efficacy of recombinant human erythropoietin (rHuEPO), 11 of darbepoetin alpha (DA) and 3 of continuous erythropoietin receptor activator (CERA), with 6 studies appraising secondary outcome measures exclusively. Recruitment to studies was a consistent challenge. The most common adverse effect was hypertension, although confounding effects often limited direct correlation. Two large cohort studies demonstrated a greater hazard of death independently associated with high ESA dose. Secondary outcome measures included quality of life measures, growth and nutrition, exercise capacity, injection site pain, cardiovascular function, intelligent quotient, evoked potentials and platelet function.
All ESA preparations and modes of administration were efficacious, with evidence of harm at higher doses. Evidence supports individualizing treatments, with strong consideration given to alternate treatments in patients who appear resistant to ESA therapy. Further research should focus on randomized trials comparing the efficacy of different preparations, treatment options in apparently ESA-resistant cohorts and clarification of meaningful secondary outcomes to consolidate patient-relevant indices.
促红细胞生成素（ESAs）在20世纪80年代末被引入时，彻底改变了慢性肾脏病（CKD）贫血的管理方式。现在有一系列的ESA类型、制剂和给药方式，新型药物给药频率更低。尽管已发表了针对成人的系统评价和荟萃分析，但尚未进行关于儿童ESAs的系统评价。
采用系统评价和荟萃分析的首选报告项目声明来进行系统评价。检索了所有关于CKD儿童ESAs相关结局的可用文献。由两名独立审阅者对MEDLINE、CINAHL和Embase数据库进行检索。纳入标准为以英文发表的试验、患有慢性和终末期肾病的儿童以及使用任何一种ESA并针对任何结局指标进行研究。使用Cochrane干预措施系统评价手册中的标准对所有纳入的随机试验进行偏倚风险评估。使用两个表格对随机试验和观察性研究进行数据提取。研究类型、参与者、纳入标准、病例特征、随访时间、ESA类型和剂量、干预措施和结局由一名作者提取。
在965篇已识别的文章中，纳入了58篇，涵盖54个队列。6篇为随机试验，48篇为观察性研究。共有38项研究评估了重组人促红细胞生成素（rHuEPO）的疗效，11项评估了阿法达贝泊汀（DA）的疗效，3项评估了持续促红细胞生成素受体激活剂（CERA）的疗效，6项研究仅评估了次要结局指标。研究招募一直是个挑战。最常见的不良反应是高血压，尽管混杂效应常常限制了直接相关性。两项大型队列研究表明，高ESA剂量独立地与更高的死亡风险相关。次要结局指标包括生活质量指标、生长和营养、运动能力、注射部位疼痛、心血管功能、智商、诱发电位和血小板功能。
所有ESA制剂和给药方式均有效，但高剂量时有危害证据。有证据支持个体化治疗，对于似乎对ESA治疗耐药的患者应充分考虑替代治疗。进一步的研究应侧重于比较不同制剂疗效的随机试验、明显对ESA耐药队列的治疗选择以及明确有意义的次要结局以巩固与患者相关的指标。
