A multicentre prospective double blinded randomised controlled trial of intravenous iron (ferric Derisomaltose (FDI)) in Iron deficient but not anaemic patients with chronic kidney disease on functional status

Abstract

Background Iron deficiency (ID) is common in patients with chronic kidney disease (CKD). Intravenous (IV) iron in heart failure leads to improvement in exercise capacity and improvement in quality-of-life measurements; however, data in patients with CKD are lacking. Methods The Iron and the Heart Study was a prospective double blinded randomised study in non-anaemic CKD stages 3b-5 patients with ID which investigated whether 1000 mg of IV iron (ferric derisomaltose (FDI)) could improve exercise capacity in comparison to placebo measured at 1 and 3 months post infusion. Secondary objectives included effects on haematinic profiles and haemoglobin, safety analysis and quality of life questionnaires (QoL). Results We randomly assigned 54 patients mean (SD) age for FDI (n = 26) 61.6 (10.1) years vs placebo (n = 28; 57.8 (12.9) years) and mean eGFR (33.2 (9.3) vs. 29.1 (9.6) ml/min/1.73m2) at baseline, respectively. Adjusting for baseline measurements, six-minute walk test (6MWT) showed no statistically significant difference between arms at 1 month (p = 0.736), or 3 months (p = 0.741). There were non-significant increases in 6MWT from baseline to 1 and 3 months in the FDI arm. Haemoglobin (Hb) at 1 and 3 months remained stable. There were statistically significant increases in ferritin (SF) and transferrin saturation (TSAT) at 1 and 3 months (p < 0.001). There was a modest numerical improvement in QoL parameters. There were no adverse events attributable to IV iron. Conclusion This study demonstrated a short-term beneficial effect of FDI on exercise capacity, but it was not significant despite improvements in parameters of iron status, maintenance of Hb concentration, and numerical increases in functional capacity and quality of life scores. A larger study will be required to confirm if intravenous iron is beneficial in iron deficient non-anaemic non-dialysis CKD patients without heart failure to improve the 6MWT. Trial registration European Clinical Trials Database (EudraCT) No: 2014-004133-16 REC no: 14/YH/1209 Date First Registered: 2015-02-17 and date of end of trail 2015-05-23 Sponsor ref R1766 and Protocol No: IHI 141

Causal associations between iron status and sepsis: a Mendelian randomisation analysis

“…One previous study has used two sample Mendelian randomisation to evaluate the relationship between iron biomarkers and sepsis, using a smaller cohort for identification of variants, and using a previously performed GWAS of sepsis in UK Biobank. 31 In common with our study, they identified associations with iron biomarkers and the odds of sepsis (OR for iron = 1.21, 95% CI = 1.13–1.29, p = 3.16 × 10 −4 ). However, this study included much fewer SNPs, as the GWAS used was around five to ten times smaller (n = 23,986 vs n = 246,139 for ferritin), meaning that only two SNPs were included for iron status, and three SNPS included for transferrin saturation and ferritin.…”

“…The odds ratio for sepsis with each increasing standard deviation of TSAT from our meta-analysis of both cohorts (1.11, 95% CI 1.05-1.20), should be put in the context that taking an oral iron supplement transiently increases TSAT by around 2-3 standard deviations for around 8 hours 35 ; while intravenous iron increases TSAT by around a standard deviation for at least three months in non-anaemic populations with chronic kidney disease. 36…”

“…The odds ratio for sepsis with each increasing standard deviation of TSAT from our meta-analysis of both cohorts (1.11, 95% CI 1.05-1.20), should be put in the context that taking an oral iron supplement transiently increases TSAT by around 2-3 standard deviations for around 8 hours 35 ; while intravenous iron increases TSAT by around a standard deviation for at least three months in non-anaemic populations with chronic kidney disease. 36 One recent experimental study explored the effect of oral iron supplementation on bacterial growth in healthy adults, and identified an increase in TSAT from 42.1% (SD 12.5%) to 75.7% (SD 18%) and total serum iron increased from 30.3 μmol/L (SD 10.2) to 53.0μmol/L (SD 15.8) at four hours after iron supplementation, and identified TSAT as the key driver of bacterial growth, with positive associations at all levels of transferrin saturation.…”

Impact of intravenous iron on cardiac and skeletal oxidative stress and cardiac mitochondrial function in experimental uraemia chronic kidney disease

“…A 4 trial metaanalysis also suggested treatment with intravenous ferric carboxymaltose was associated with a reduction in recurrent cardiovascular hospitalisations in systolic heart failure patients [21]. Also, in iron deficient non anaemic chronic kidney disease patients a recent randomised controlled trial suggested a trend to an improved quality of life and reduction in brain naturetic peptide (BNP) [22]. Anaemia significantly increases the risk of morbidity and mortality in CKD [12].…”

The effect of intravenous iron supplementation on exercise capacity in iron-deficient but not anaemic patients with chronic kidney disease: study design and baseline data for a multicentre prospective double-blind randomised controlled trial

“…However, a recently published study in non-dialysis kidney patients who were non-anaemic but iron deficient did not report any statistical significant beneficial effect of iron therapy on exercise capacity at 4 or 12 weeks, but did show numerical improvements in exercise capacity measurement in the iron therapy group [ 13 ]. This trial had a small sample size and there were imbalances in baseline exercise capacity between groups, which may account for the non-significant outcome.…”