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Guideline 2.5 – Treatment of Iron Deficiency without Anaemia

Guideline 2.5 – Treatment of Iron Deficiency without Anaemia

We recommend for people with chronic kidney disease with iron deficiency without anaemia and concomitant heart failure administration of IV iron to improve well-being, physical function, and to reduce heart failure admissions. (1A)

Guideline 2.5.1

We suggest for people with CKD with iron deficiency but without anaemia and no concomitant heart failure, a trial of oral or IV iron for improvement in clinical symptoms such as restless legs. (2B)

Rationale

Iron Deficiency and no Anaemia

It is not known whether treatment of people with CKD and Hb values >120 g/L in the presence of iron deficiency is beneficial. The Iron and Heart multicentre double-blinded randomised controlled clinical trial examined the effects of a single dose of intravenous iron vs. placebo on functional capacity using the 6-minute walk test, in non-anaemic iron deficient people (serum ferritin <100 μg/L and/or TSAT<20%) with NDD-CKD stage 3b-5. 54 individuals were randomised to receive ferric derisomaltose (n = 26) or placebo (n = 28) (1-3). Secondary analysis showed no impact on markers of oxidative stress, inflammation, and endothelial function. There was a modest but statistically significant rise in E-selectin in the IV iron group at 1-month and 3-month follow-up (p = 0.030 and p = 0.002 respectively). These results suggest ferric derisomaltose administration in people with NDD-CKD iron deficient does not induce prolonged oxidative stress or inflammation. These preliminary secondary analyses suggest larger trials are required to quantify the benefit of IV iron administration in this group.

The FAIR-HF trial enrolled 459 participants with NYHA class II or III, iron deficiency (ferritin <100 μg/l or between 100 and 299 μ g/l if TSATs <20%), Hb 95 – 135 g/L (4). Participants were randomised to receive 200 mg of IV iron (ferric carboxymaltose) or saline. The primary end points were NYHA functional class and self-reported Patient Global Assessment at 24 weeks. The distance walked in 6 minutes was a secondary end point. Participants receiving ferric carboxymaltose, 50% reported being much or moderately improved on the Patient Global Assessment as compared to 28% of participants receiving placebo (OR, 2.51; 95% CI: 1.75 to 3.61). In the ferric carboxymaltose group, 47% had a NYHA functional class I or II at week 24, as compared with 30% of participants assigned placebo (OR for improvement by one class, 2.40; 95% CI: 1.55 to 3.71). Significant improvements were seen in distance on 6-minute walk test. In a sub-group analysis, the benefits of ferric carboxymaltose were seen in people with eGFR both above and less than 60 ml/min/1.73m2.

The CONFIRM-HF trial enrolled 304 symptomatic participants with heart failure with left ventricular ejection fraction < or = 45%, elevated natriuretic peptides, and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL if TSATS <20%) (5). Participants were randomised to either IV iron (ferric carboxymaltose, given as 500 or 1000 mg) or placebo. The primary end point was 6-min-walk-test (6MWT) distance from baseline to week 24. Treatment with FCM significantly prolonged 6MWT at week 24 (difference FCM vs. placebo: 33 ± 11 m, p = 0.002). The finding was consistent across all sub-groups including those with eGFR < 60 mL/min/1.73m2.

The IRONMAN trial was a randomised controlled trial in the UK of people with heart failure (LV ejection fraction < or equal to 45%) and TSATs < 20% or serum ferritin < 100 μg/L were eligible (6). 1137 were enrolled and randomly assigned to receive ferric derisomaltose or usual care. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death. 336 primary endpoints (22.4 per 100 patient years) occurred in the ferric derisomaltose group and 4111 (27.5 per 100 patient years) in the placebo group (RR 0.82 (0.66 – 1.02) p = 0.070. In the COVID 19 analysis (censoring f/u on Sept 30th 2020) 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI: 0·58 to 1·00]; p=0·047). In a subgroup analysis there was no difference between those with eGFR above or below 60 mL/min/1.73m2. For < 60 mL/min/1.73m2 group there were 248 events (26.86 per 100 patient-years) in the ferric derisomaltose group compared to 318 events (35.36 per 100 patient years) in the placebo group (RR 0.77 [0.60-0.98].

The Iron and Heart trial and the Iron and Muscle trial both randomised participants to intravenous iron (ferric derisomaltose and ferric carboxymaltose in the two studies respectively (2, 7). Both recruited participants with CKD (eGFR < 60 mL/min/1.73m2) and defined iron deficiency as a ferritin < 100μg/L and/or TSATs < 20%. Both used 6MWT distance one month as the primary outcome. Iron and Heart recruited 54 participants and the Iron and Muscle trial recruited 75. Adjusting for baseline 6MWT there was no statistically significant difference in 6MWT distance at 1 month in either study (p = 0.26 and 0.74 in the two studies respectively). A subgroup in the Iron and Muscle trial had mitochondrial function assessed by two methodologies: respirometry and by 31-phosphorus magnetic resonance spectroscopy. There was no difference in mitochondrial function between placebo and iron groups at 1 month (p = 0.84 and 0.84 for the two methodologies respectively).

In a systematic review of iron-deficient but not anaemic adults, iron supplementation was associated with and improvement in subjective measures of fatigue but not with objective improvements in physical capacity, as determined by aerobic tests. It should be noted that people with CKD were not specifically included or analysed in the studies examined (8).

Two randomised controlled trials explored the use of IV iron in the treatment of restless leg syndrome (RLS) in HD patients. They both identified a significant but transient improvement in symptoms. However, since IV iron is now an established treatment in haemodialysis they have limited impact (9, 10).

They were both included in a systematic review which found that treatment of RLS with iron was associated with an increased rate of adverse events RR 2.04 (95% CI: 1.46–2.85), however these were not severe and not associated with treatment discontinuation. Overall, iron supplementation was associated with improvement of RLS (11).

Guedes and colleagues (12, 13) have shown a direct association with biomarkers of iron stores with worse physical health-related quality of life in NDD-CKD patients with or without anaemia and also an association with increased risk of all-cause mortality and cardiovascular events in people with NDD-CKD, with or without anaemia. Some have suggested consideration of treatment or people with “profound iron deficiency defined as a serum ferritin of <30 mcg/L and TSAT <16% but data is lacking to confirm this.

References

  1. Bhandari, S., Allgar, V., Lamplugh, A., MacDougall, I. C. & Kalra, P. A. Protocol and Baseline data of a multicentre prospective double-blinded randomized study of intravenous iron on functional status in patients with chronic kidney disease. Am. J. Nephrol. 51, 493–500 (2020).
  2. Bhandari, S., Allgar, V., Lamplugh, A., Macdougall, I. & Kalra, P. A. 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 function status. BMC Nephrol. 22 (2021).(1); 115
  3. Kassianides X, Allgar V, Macdougall IV, Kalra PA, Bhandari S. Analysis of oxidative stress, inflammation and endothelial function following intravenous iron in chronic kidney disease in the Iron and Heart Trial. Scientific Reports | (2022) 12:6853 | https://doi.org/10.1038/s41598-022-10717-8
  4. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency. N Engl J Med. 2009 Dec 17;361(25):2436–48.
  5. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015 Mar 14;36(11):657–68.
  6. Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet Lond Engl. 2022 Dec 17;400(10369):2199–209.
  7. Greenwood SA, Oliveira BA, Asgari E, Ayis S, Baker LA, Beckley-Hoelscher N, Goubar A, Banerjee D, Bhandari S, Chilcot, Burton JO, Kalra PA, Lightfoot CJ, Macdougall IC, McCafferty K, Mercer TH, Okonko DO, Reid1 C, Reid F, Smith AC, Swift PA, Mangelis A, Watson E, Wheeler DC, Wilkinson TJ, Bramham K. A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD. Kidney International Reports. 2023 8, 1496–1505
  8. Houston BL, Hurrie D, Graham J, et al. Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials. BMJ Open. 2018;8:e019240.
  9. Deng Y, Wu J, Jia Q. Efficacy of intravenous Iron sucrose in hemodialysis patients with restless legs syndrome (RLS): A randomized, placebo-controlled study. Medical Sci Monit, 2017;23:1254–60.
  10. Sloand JA, Shelly MA, Feigin A, Bernstein P, Monk RD. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kind Dis 2004;43(4):663–70.
  11. Avni T, Reich S, Lev N, et al. Iron supplementation for restless legs syndrome—a systematic review and meta-analysis. Eur J Intern Med. 2019;63:34–41.
  12. Guedes M, Muenz D, Zee J, et al. Serum biomarkers of iron stores are associated with worse physical health-related quality of life in nondialysis-dependent chronic kidney disease patients with or without anemia. Nephrol Dial Transplant. 2021;36:1694–1703.
  13. Guedes M, Muenz DG, Zee J, et al. Serum biomarkers of iron stores are associated with increased risk of all-cause mortality and cardiovascular events in nondialysis CKD patients, with or without anemia. J Am Soc Nephrol. 2021;32:2020–2030.