Supplementary Material for: Protocol and Baseline Data of a Multicentre Prospective Double-Blinded Randomized Study of Intravenous Iron on Functional Status in Patients with Chronic Kidney Disease

<b><i>Background:</i></b> Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) due to an inadequate dietary intake of iron, poor absorption from the gut and increased iron losses. In addition to preventing anaemia, iron is important for normal heart function, being involved in processes that generate a necessary continuous energy supply. Treatment with intravenous (IV) iron has been suggested to lead to improvement in heart function and well-being in people with ID and CKD. In the Iron and the Heart Study, we hypothesized that IV iron treatment will primarily improve exercise capacity and may secondarily impact the feeling of well-being in comparison to placebo over 3 months in non-anaemic CKD patients who have ID. <b><i>Methods:</i></b> This was a prospective double-blinded explorative randomized, multi-centre study designed to compare the effects of IV iron supplementation and placebo in iron-deficient but not anaemic patients with established CKD stages 3b-5 on functional status, and in addition cardiac structure and function. The study included 54 adults with serum ferritin (SF) &lt;100 µg/L and/or transferrin saturation &lt;20%, randomized in a 1:1 ratio to 1,000 mg IV ferric derisomaltose or placebo. Following randomization, participants underwent baseline assessments and then received IV iron or placebo infusion. Each participant was followed up at months 1 and 3. At each visit, patients underwent clinical review, measurements of hematinics and haemoglobin (Hb), and assessments of physical function and well-being. The primary outcome was exercise capacity using the 6-minute walk test. Secondary objectives included effects on hematinic profiles and Hb concentration, changes in myocardial parameters assessed with speckle tracking echocardiography and change in patients’ quality of life. <b><i>Results:</i></b> Between October 2016 and April 2018, 55 from 326 individuals from 3 UK centres attended screening and were randomized. The mean (SD) age was 59.6 (11.7) years, 26 (48%) patients were male, the majority were Caucasians (42; 78%), and 32 (59%) were non-smokers. The mean (SD) body mass index was 30.3 (6.5); SF was 66.3 (44.1) µg/L, TS was 20.1 (7.4) % and Hb was 128.7 (10.1) g/L at randomization for the whole group. Mean (SD) serum creatinine was 186.7 (58.6) µmol/L, estimated glomerular filtration rate was 31.1 (9.6) mL/min/1.73 m² and urinary albumin and protein/creatinine ratios 60.9 (133.3) and 83.8 (128.4) mg/mmol respectively. The mean (SD) C-reactive protein was 5.0 (4.4) mg/L and the mean (SD) 6-minute walk distance at baseline was 401.2 (120.2) m. <b><i>Conclusion:</i></b> The Iron and the Heart Trial will provide important information on the short-term effects of IV iron treatment in CKD patients with ID without anaemia on measures of exercise capacity, quality of life and mechanistic data on myocardial structure and function. <b><i>Trial Registration:</i></b> European Clinical Trials Database (No. 2014-004133-6; REC no. 14/YH/1209; Sponsor ref. R1766).

<b><i>背景：</i></b> 铁缺乏（iron deficiency, ID）在慢性肾脏病（chronic kidney disease, CKD）患者中十分常见，其诱因包括铁摄入不足、肠道吸收不良以及铁丢失增加。除预防贫血外，铁对于维持正常心脏功能亦至关重要，其参与了维持机体持续能量供给的关键生理过程。有研究提示，静脉（intravenous, IV）铁治疗可改善铁缺乏合并慢性肾脏病患者的心脏功能与健康状态。本项“铁与心脏研究”（Iron and the Heart Study）提出假设：在合并铁缺乏但无贫血的慢性肾脏病患者中，与安慰剂相比，为期3个月的静脉铁治疗可首要改善患者的运动能力，并可次要改善其健康感知状态。<b><i>方法：</i></b> 本研究为一项前瞻性、双盲、探索性、多中心随机对照试验，旨在对比静脉铁补充剂与安慰剂对确诊为CKD 3b-5期的铁缺乏非贫血患者的功能状态、心脏结构与功能的影响。研究共纳入54名成人受试者，其血清铁蛋白（serum ferritin, SF）＜100 μg/L，和/或转铁蛋白饱和度（transferrin saturation, TS）＜20%，以1:1的比例随机分组，接受1000 mg异麦芽糖酐铁（ferric derisomaltose）静脉输注或安慰剂输注。受试者完成基线评估后接受对应干预，并分别于第1、3个月进行随访。每次随访均对患者进行临床评估，检测血液学指标与血红蛋白（haemoglobin, Hb）水平，并评估其躯体功能与健康状态。本研究的主要结局指标为采用6分钟步行试验（6-minute walk test）测得的运动能力。次要研究目标包括对血液学指标与血红蛋白浓度的影响、斑点追踪超声心动图（speckle tracking echocardiography）评估的心肌参数变化，以及患者生活质量的改变。<b><i>结果：</i></b> 2016年10月至2018年4月期间，来自英国3家研究中心的326名受试者中，共有55名完成筛查并被随机分组。全组受试者的平均年龄（标准差）为59.6（11.7）岁，其中男性26例（占比48%）；绝大多数为白种人（42例，占比78%），非吸烟者32例（占比59%）。全组受试者随机分组时的平均体质指数（标准差）为30.3（6.5）；血清铁蛋白为66.3（44.1）μg/L，转铁蛋白饱和度为20.1（7.4）%，血红蛋白为128.7（10.1）g/L。平均血清肌酐（标准差）为186.7（58.6）μmol/L，估算肾小球滤过率（estimated glomerular filtration rate）为31.1（9.6）mL/min/1.73 m²，尿白蛋白与尿蛋白/肌酐比值分别为60.9（133.3）与83.8（128.4）mg/mmol。全组受试者基线时的平均C反应蛋白（C-reactive protein）水平为5.0（4.4）mg/L，平均基线6分钟步行距离为401.2（120.2）m。<b><i>结论：</i></b> “铁与心脏试验”（Iron and the Heart Trial）将为合并铁缺乏的非贫血慢性肾脏病患者提供重要信息，阐明静脉铁治疗对该人群运动能力、生活质量的短期影响，以及其对心肌结构与功能的机制性数据。<b><i>试验注册：</i></b> 欧洲临床试验数据库（编号：2014-004133-6；REC编号：14/YH/1209；申办方编号：R1766）。