A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease

Sharlene A. Greenwood; Benjamin A Oliveira; Elham Asgari; Salma Ayis; Luke A Baker; Nick Beckley-Hoelscher; Aicha Goubar; Debasish Banerjee; Sunil Bhandari; Joseph Chilcot; James O Burton; Philip A Kalra; C.J Lightfoot; Iain C Macdougall; Kieran McCafferty; Thomas H. Mercer; Darlington O Okonko; Chante Reid; Fiona Reid; Alice C. Smith; Pauline A. Swift; Emma Watson; David C. Wheeler; Thomas J  Wilkinson; Kate Bramham

doi:10.1016/j.ekir.2023.05.002

A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease

Sharlene A. Greenwood, Benjamin A Oliveira, Elham Asgari, Salma Ayis, Luke A Baker, Nick Beckley-Hoelscher, Aicha Goubar, Debasish Banerjee, Sunil Bhandari, Joseph Chilcot, James O Burton, Philip A Kalra, C.J Lightfoot, Iain C Macdougall, Kieran McCafferty, Thomas H. Mercer, Darlington O Okonko, Chante Reid, Fiona Reid, Alice C. SmithPauline A. Swift, Emma Watson, David C. Wheeler, Thomas J Wilkinson, Kate Bramham

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Abstract

Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m ²], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) μg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

Original language	English
Pages (from-to)	1496-1505
Number of pages	10
Journal	Kidney International Reports
Volume	8
Issue number	8
DOIs	https://doi.org/10.1016/j.ekir.2023.05.002
Publication status	Published - 9 May 2023

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Iron and Muscle CKD Final published version, 276 KBLicence: CC BY-NC-ND

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Greenwood, S. A., Oliveira, B. A., Asgari, E., Ayis, S., Baker, L. A., Beckley-Hoelscher, N., Goubar, A., Banerjee, D., Bhandari, S., Chilcot, J., Burton, J. O., Kalra, P. A., Lightfoot, C. J., Macdougall, I. C., McCafferty, K., Mercer, T. H., Okonko, D. O., Reid, C., Reid, F., ... Bramham, K. (2023). A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease. Kidney International Reports, 8(8), 1496-1505. https://doi.org/10.1016/j.ekir.2023.05.002

@article{f0b9ae4f970f4947bab7db8f9941fad9,

title = "A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease",

abstract = "Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m 2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) μg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.",

author = "Greenwood, {Sharlene A.} and Oliveira, {Benjamin A} and Elham Asgari and Salma Ayis and Baker, {Luke A} and Nick Beckley-Hoelscher and Aicha Goubar and Debasish Banerjee and Sunil Bhandari and Joseph Chilcot and Burton, {James O} and Kalra, {Philip A} and C.J Lightfoot and Macdougall, {Iain C} and Kieran McCafferty and Mercer, {Thomas H.} and Okonko, {Darlington O} and Chante Reid and Fiona Reid and Smith, {Alice C.} and Swift, {Pauline A.} and Emma Watson and Wheeler, {David C.} and Wilkinson, {Thomas J} and Kate Bramham",

note = "Funding Information: This was an investigator-led multicenter double-blind randomized placebo-controlled trial of patients with stages 3 to 4 CKD and iron-deficiency, but without anemia, aged 18 or over. The study design, flow of participants through the trial and methods have previously been reported. 21 The trial was funded by Kidney Research UK and supported by an unrestricted grant from Vifor (with donation of ferric carboxymaltose for the trial). Brent Ethics Committee approved the protocol (19/LO/0128) and the study was prospectively registered (EudraCT: 2018-000144-25 on 28/01/2019). Funding Information: The authors acknowledge the work of the various research teams at each site. The trial was funded by Kidney Research UK and supported by an unrestricted grant from Vifor (with donation of ferric carboxymaltose for the trial). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, Kidney Research UK, or the Department of Health. The funders had no role in the design, collection, analysis, interpretation of the data, or writing of this protocol. Findings from the study will be disseminated at national and international conferences. All baseline data generated or analyzed during this study are included in this published article. The protocol and related documents were approved by Brent Research Ethics Committee, UK (REC) 19/LO/0128, the Health Research Authority and the UK Medicines and Healthcare products Regulatory Agency (MHRA). The study was prospectively registered on 28/01/2019 (EudraCT 2018-000144-25). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and/or their legal guardian(s). Authorship followed ICMJE guidelines. SG, DO, NB, FR, EW, TW, AS, and ICM were responsible for the inception and design of the project and prepared the manuscript. SG, NB, EA, JC, KM, DO, AM, SB, JB, ICM, PK, CR, PS, DB, DW, CL, LB, BO, KB, FR, SA, TM, AM, AG contributed to the design of the study, provided methodological input, and wrote the manuscript text and prepared tables. All authors reviewed the manuscript. Publisher Copyright: {\textcopyright} 2023 International Society of Nephrology",

year = "2023",

month = may,

day = "9",

doi = "10.1016/j.ekir.2023.05.002",

language = "English",

volume = "8",

pages = "1496--1505",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier Inc.",

number = "8",

}

Greenwood, SA, Oliveira, BA, Asgari, E, Ayis, S, Baker, LA, Beckley-Hoelscher, N , Goubar, A, Banerjee, D, Bhandari, S, Chilcot, J, Burton, JO, Kalra, PA, Lightfoot, CJ, Macdougall, IC, McCafferty, K, Mercer, TH, Okonko, DO, Reid, C, Reid, F, Smith, AC, Swift, PA, Watson, E, Wheeler, DC, Wilkinson, TJ & Bramham, K 2023, 'A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease', Kidney International Reports, vol. 8, no. 8, pp. 1496-1505. https://doi.org/10.1016/j.ekir.2023.05.002

TY - JOUR

T1 - A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease

AU - Greenwood, Sharlene A.

AU - Oliveira, Benjamin A

AU - Asgari, Elham

AU - Ayis, Salma

AU - Baker, Luke A

AU - Beckley-Hoelscher, Nick

AU - Goubar, Aicha

AU - Banerjee, Debasish

AU - Bhandari, Sunil

AU - Chilcot, Joseph

AU - Burton, James O

AU - Kalra, Philip A

AU - Lightfoot, C.J

AU - Macdougall, Iain C

AU - McCafferty, Kieran

AU - Mercer, Thomas H.

AU - Okonko, Darlington O

AU - Reid, Chante

AU - Reid, Fiona

AU - Smith, Alice C.

AU - Swift, Pauline A.

AU - Watson, Emma

AU - Wheeler, David C.

AU - Wilkinson, Thomas J

AU - Bramham, Kate

N1 - Funding Information: This was an investigator-led multicenter double-blind randomized placebo-controlled trial of patients with stages 3 to 4 CKD and iron-deficiency, but without anemia, aged 18 or over. The study design, flow of participants through the trial and methods have previously been reported. 21 The trial was funded by Kidney Research UK and supported by an unrestricted grant from Vifor (with donation of ferric carboxymaltose for the trial). Brent Ethics Committee approved the protocol (19/LO/0128) and the study was prospectively registered (EudraCT: 2018-000144-25 on 28/01/2019). Funding Information: The authors acknowledge the work of the various research teams at each site. The trial was funded by Kidney Research UK and supported by an unrestricted grant from Vifor (with donation of ferric carboxymaltose for the trial). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, Kidney Research UK, or the Department of Health. The funders had no role in the design, collection, analysis, interpretation of the data, or writing of this protocol. Findings from the study will be disseminated at national and international conferences. All baseline data generated or analyzed during this study are included in this published article. The protocol and related documents were approved by Brent Research Ethics Committee, UK (REC) 19/LO/0128, the Health Research Authority and the UK Medicines and Healthcare products Regulatory Agency (MHRA). The study was prospectively registered on 28/01/2019 (EudraCT 2018-000144-25). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and/or their legal guardian(s). Authorship followed ICMJE guidelines. SG, DO, NB, FR, EW, TW, AS, and ICM were responsible for the inception and design of the project and prepared the manuscript. SG, NB, EA, JC, KM, DO, AM, SB, JB, ICM, PK, CR, PS, DB, DW, CL, LB, BO, KB, FR, SA, TM, AM, AG contributed to the design of the study, provided methodological input, and wrote the manuscript text and prepared tables. All authors reviewed the manuscript. Publisher Copyright: © 2023 International Society of Nephrology

PY - 2023/5/9

Y1 - 2023/5/9

N2 - Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m 2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) μg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

AB - Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m 2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) μg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

UR - http://www.scopus.com/inward/record.url?scp=85162259957&partnerID=8YFLogxK

U2 - 10.1016/j.ekir.2023.05.002

DO - 10.1016/j.ekir.2023.05.002

M3 - Article

SN - 2468-0249

VL - 8

SP - 1496

EP - 1505

JO - Kidney International Reports

JF - Kidney International Reports

IS - 8

ER -

A randomized trial of intravenous iron supplementation and exercise on exercise capacity in iron-deficient non-anemic patients with chronic kidney disease

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