1.
Use of erythropoiesis-stimulating agents in children with chronic kidney disease: a systematic review
Bruce G, Schulga P, Reynolds BC
Clinical kidney journal. 2022;15(8):1483-1505
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Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
PICO Summary
Population
Children with chronic kidney disease using any erythropoiesis-stimulating agents (ESAs), (58 studies, n= 3,895).
Intervention
Systematic review assessing the efficacy of ESAs.
Comparison
Outcome
A total of 38 studies assessed the efficacy of recombinant human erythropoietin, 11 of darbepoetin alpha, and 3 of continuous erythropoietin receptor activator, with 6 studies appraising secondary outcome measures exclusively. 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.
2.
Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection for the treatment of renal anemia in Chinese hemodialysis patients: A randomized, open-label, parallel-group, noninferiority phase III trial
Liu B, Chen N, Zhao J, Yin A, Wu X, Xing C, Jiang G, Fu J, Wang M, Wang R, et al
Chronic diseases and translational medicine. 2022;8(2):134-144
Abstract
BACKGROUND This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection, rHuEPO) for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis. METHOD This study was a multicenter, randomized, open-label, intergroup parallel control phase III noninferiority trial from April 19, 2013 to September 9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks. The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week. All subjects underwent epoetin alfa administration during the 8-week baseline period. After that, subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group. The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was tested between the two treatments. The time-dependent hemoglobin (Hb) concentration and the maintenance rate of the target Hb concentration (the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were also evaluated. Iron metabolism, including changes in the serum iron, total iron-binding capacity, ferritin, transferrin saturation, and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further. Adverse events (AEs) were also observed and compared, and the safety was analyzed between the two treatment groups. The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. RESULTS Four hundred and sixty-six patients were enrolled in this study, and ultimately 384 cases were analyzed for safety, including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211 cases in the per-protocol set, including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group. The changes in the average Hb concentrations from the baseline to the end of the evaluation period were -0.07 and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively. The difference between the two groups was 0.08 g/dl (95% confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was -0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were 10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during the study period of Weeks 0-28, with the maintenance rates of the target Hb concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group and epoetin alfa group respectively. During the period of comparison between the two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while in the epoetin alfa group it was 56.41%. All of the adverse events and reactions in the study were those commonly associated with hemodialysis. CONCLUSION The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.
3.
Parenteral versus oral iron therapy for adults and children with chronic kidney disease
O'Lone EL, Hodson EM, Nistor I, Bolignano D, Webster AC, Craig JC
The Cochrane database of systematic reviews. 2019;2:Cd007857
Abstract
BACKGROUND The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. This is an update of a review first published in 2012. OBJECTIVES To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD, including participants on dialysis, with kidney transplants and CKD not requiring dialysis. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs in which IV and oral routes of iron administration were compared in adults and children with CKD. DATA COLLECTION AND ANALYSIS Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. The certainty of the evidence was assessed using GRADE. MAIN RESULTS We included 39 studies (3852 participants), 11 of which were added in this update. A low risk of bias was attributed to 20 (51%) studies for sequence generation, 14 (36%) studies for allocation concealment, 22 (56%) studies for attrition bias and 20 (51%) for selective outcome reporting. All studies were at a high risk of performance bias. However, all studies were considered at low risk of detection bias because the primary outcome in all studies was laboratory-based and unlikely to be influenced by lack of blinding.There is insufficient evidence to suggest that IV iron compared with oral iron makes any difference to death (all causes) (11 studies, 1952 participants: RR 1.12, 95% CI 0.64, 1.94) (absolute effect: 33 participants per 1000 with IV iron versus 31 per 1000 with oral iron), the number of participants needing to start dialysis (4 studies, 743 participants: RR 0.81, 95% CI 0.41, 1.61) or the number needing blood transfusions (5 studies, 774 participants: RR 0.86, 95% CI 0.55, 1.34) (absolute effect: 87 per 1,000 with IV iron versus 101 per 1,000 with oral iron). These analyses were assessed as having low certainty evidence. It is uncertain whether IV iron compared with oral iron reduces cardiovascular death because the certainty of this evidence was very low (3 studies, 206 participants: RR 1.71, 95% CI 0.41 to 7.18). Quality of life was reported in five studies with four reporting no difference between treatment groups and one reporting improvement in participants treated with IV iron.IV iron compared with oral iron may increase the numbers of participants, who experience allergic reactions or hypotension (15 studies, 2607 participants: RR 3.56, 95% CI 1.88 to 6.74) (absolute harm: 24 per 1000 with IV iron versus 7 per 1000) but may reduce the number of participants with all gastrointestinal adverse effects (14 studies, 1986 participants: RR 0.47, 95% CI 0.33 to 0.66) (absolute benefit: 150 per 1000 with IV iron versus 319 per 1000). These analyses were assessed as having low certainty evidence.IV iron compared with oral iron may increase the number of participants who achieve target haemoglobin (13 studies, 2206 participants: RR 1.71, 95% CI 1.43 to 2.04) (absolute benefit: 542 participants per 1,000 with IV iron versus 317 per 1000 with oral iron), increased haemoglobin (31 studies, 3373 participants: MD 0.72 g/dL, 95% CI 0.39 to 1.05); ferritin (33 studies, 3389 participants: MD 224.84 microg/L, 95% CI 165.85 to 283.83) and transferrin saturation (27 studies, 3089 participants: MD 7.69%, 95% CI 5.10 to 10.28), and may reduce the dose required of erythropoietin-stimulating agents (ESAs) (11 studies, 522 participants: SMD -0.72, 95% CI -1.12 to -0.31) while making little or no difference to glomerular filtration rate (8 studies, 1052 participants: 0.83 mL/min, 95% CI -0.79 to 2.44). All analyses were assessed as having low certainty evidence. There were moderate to high degrees of heterogeneity in these analyses but in meta-regression, definite reasons for this could not be determined. AUTHORS' CONCLUSIONS The included studies provide low certainty evidence that IV iron compared with oral iron increases haemoglobin, ferritin and transferrin levels in CKD participants, increases the number of participants who achieve target haemoglobin and reduces ESA requirements. However, there is insufficient evidence to determine whether IV iron compared with oral iron influences death (all causes), cardiovascular death and quality of life though most studies reported only short periods of follow-up. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes with longer follow-up periods are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects.
4.
Short term correction of anaemia with recombinant human erythropoietin and reduction of cardiac output in end stage renal failure
Morris KP, Skinner JR, Hunter S, Coulthard MG
Archives of Disease in Childhood. 1993;68((5):):644-8.
Abstract
Children with end stage renal failure and anaemia have an increased cardiac index and often gross ventricular hypertrophy. The contribution of anaemia to these abnormalities is uncertain. Eleven children with end stage renal failure and anaemia (haemoglobin concentration < 90 g/l) were enrolled into a single blind, placebo controlled, crossover study to assess the cardiovascular effects of reversing anaemia using subcutaneous human recombinant erythropoietin (r-HuEpo). Each limb lasted 24 weeks; seven children completed both limbs of the study. Haemoglobin increased with r-HuEpo, remaining above 100 g/l for a mean of 11 weeks. Cardiac index fell as a result of a reduction in both left ventricular stroke volume and heart rate. Left ventricular end diastolic diameter also decreased. In five children left ventricular wall thickness and left ventricular mass decreased with r-HuEpo, but this failed to reach significance for the whole group. Blood pressure did not change in six normotensive children completing an r-HuEpo limb; the decrease in cardiac index was therefore balanced by an increase in peripheral vascular resistance. Three children were taking anti-hypertensive treatment at the start of the study; one required an increase, and one a decrease, in treatment during the r-HuEpo limb. Short term treatment with r-HuEpo reduces cardiac index. A longer study is needed to determine whether this will, in time, result in a significant reduction in left ventricular hypertrophy.