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Published in: BMC Nephrology 1/2018

Open Access 01-12-2018 | Research article

Association of different iron deficiency cutoffs with adverse outcomes in chronic kidney disease

Authors: Michele F. Eisenga, Ilja M. Nolte, Peter van der Meer, Stephan J. L. Bakker, Carlo A. J. M. Gaillard

Published in: BMC Nephrology | Issue 1/2018

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Abstract

Background

Iron deficiency is highly prevalent in chronic kidney disease (CKD) patients. In clinical practice, iron deficiency is defined based on a combination of two commonly used markers, ferritin and transferrin saturation (TSAT). However, no consensus has been reached which cutoffs of these parameters should be applied to define iron deficiency. Hence, we aimed to assess prospectively which cutoffs of ferritin and TSAT performed optimally for outcomes in CKD patients.

Methods

We meticulously analyzed 975 CKD community dwelling patients of the Prevention of Renal and Vascular Endstage Disease prospective study based on an estimated glomerular filtration rate < 60 ml/min/1.73m2, albuminuria > 30 mg/24 h, or albumin-to-creatinine ratio ≥ 30 mg/g. Cox proportional hazard regression analyses using different sets and combinations of cutoffs of ferritin and TSAT were performed to assess prospective associations with all-cause mortality, cardiovascular mortality, and development of anemia.

Results

Of the included 975 CKD patients (62 ± 12 years, 64% male with an estimated glomerular filtration rate of 77 ± 23 ml/min/1.73m2), 173 CKD patients died during a median follow-up of 8.0 (interquartile range 7.5–8.7) years of which 70 from a cardiovascular cause. Furthermore, 164 CKD patients developed anemia. The highest risk for all-cause mortality (hazard ratio, 2.83; 95% confidence interval, 1.53–5.24), cardiovascular mortality (4.15; 1.78–9.66), and developing anemia (3.07; 1.69–5.57) was uniformly observed for a TSAT< 10%, independent of serum ferritin level.

Conclusion

In this study, we have shown that of the traditionally used markers of iron status, reduced TSAT, especially TSAT< 10%, is most strongly associated with the risk of adverse outcomes in CKD patients irrespective of serum ferritin level, suggesting that clinicians should focus more on TSAT rather than ferritin in this patient setting. Specific attention to iron levels below this cutoff seems warranted in CKD patients.
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Literature
1.
go back to reference GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545–602.CrossRef GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545–602.CrossRef
2.
go back to reference Milman N. Anemia--still a major health problem in many parts of the world! Ann Hematol. 2011;90(4):369–77.CrossRefPubMed Milman N. Anemia--still a major health problem in many parts of the world! Ann Hematol. 2011;90(4):369–77.CrossRefPubMed
3.
go back to reference McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO vitamin and mineral nutrition information system, 1993-2005. Public Health Nutr. 2009;12(4):444–54.CrossRefPubMed McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO vitamin and mineral nutrition information system, 1993-2005. Public Health Nutr. 2009;12(4):444–54.CrossRefPubMed
5.
go back to reference Bermejo F, Garcia-Lopez S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009;15(37):4638–43.CrossRefPubMedPubMedCentral Bermejo F, Garcia-Lopez S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009;15(37):4638–43.CrossRefPubMedPubMedCentral
7.
go back to reference Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. FAIR-HF Trial Investigators: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436–48.CrossRefPubMed Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. FAIR-HF Trial Investigators: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436–48.CrossRefPubMed
8.
go back to reference Macdougall IC, Bock A, Carrera F, Eckardt KU, Gaillard C, Van Wyck D, Roubert B, Cushway T, Roger SD. FIND-CKD study investigators: the FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale. Nephrol Dial Transplant. 2014;29(4):843–50.CrossRefPubMed Macdougall IC, Bock A, Carrera F, Eckardt KU, Gaillard C, Van Wyck D, Roubert B, Cushway T, Roger SD. FIND-CKD study investigators: the FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale. Nephrol Dial Transplant. 2014;29(4):843–50.CrossRefPubMed
9.
go back to reference Eisenga MF, Minovic I, Berger SP, Kootstra-Ros JE, van den Berg E, Riphagen IJ, Navis G, van der Meer P, Bakker SJ, Gaillard CA. Iron deficiency, anemia, and mortality in renal transplant recipients. Transpl Int. 2016;29(11):1176–83.CrossRefPubMed Eisenga MF, Minovic I, Berger SP, Kootstra-Ros JE, van den Berg E, Riphagen IJ, Navis G, van der Meer P, Bakker SJ, Gaillard CA. Iron deficiency, anemia, and mortality in renal transplant recipients. Transpl Int. 2016;29(11):1176–83.CrossRefPubMed
10.
go back to reference Garcia-Casal MN, Pena-Rosas JP, Pasricha SR. Rethinking ferritin cutoffs for iron deficiency and overload. Lancet Haematol. 2014;1(3):e92–4.CrossRefPubMed Garcia-Casal MN, Pena-Rosas JP, Pasricha SR. Rethinking ferritin cutoffs for iron deficiency and overload. Lancet Haematol. 2014;1(3):e92–4.CrossRefPubMed
12.
go back to reference Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel P, Swinkels DW, Wanner C, Weiss G, Chertow GM, Conference Participants. Iron management in chronic kidney disease: conclusions from a "kidney disease: improving global outcomes" (KDIGO) controversies conference. Kidney Int. 2016;89(1):28–39.CrossRefPubMed Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel P, Swinkels DW, Wanner C, Weiss G, Chertow GM, Conference Participants. Iron management in chronic kidney disease: conclusions from a "kidney disease: improving global outcomes" (KDIGO) controversies conference. Kidney Int. 2016;89(1):28–39.CrossRefPubMed
13.
go back to reference Charytan C, Levin N, Al-Saloum M, Hafeez T, Gagnon S, Van Wyck DB. Efficacy and safety of iron sucrose for iron deficiency in patients with dialysis-associated anemia: north American clinical trial. Am J Kidney Dis. 2001;37(2):300–7.CrossRefPubMed Charytan C, Levin N, Al-Saloum M, Hafeez T, Gagnon S, Van Wyck DB. Efficacy and safety of iron sucrose for iron deficiency in patients with dialysis-associated anemia: north American clinical trial. Am J Kidney Dis. 2001;37(2):300–7.CrossRefPubMed
14.
go back to reference McDonagh T, Macdougall IC. Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral? Eur J Heart Fail. 2015;17(3):248–62.CrossRefPubMedPubMedCentral McDonagh T, Macdougall IC. Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral? Eur J Heart Fail. 2015;17(3):248–62.CrossRefPubMedPubMedCentral
15.
go back to reference Shepshelovich D, Rozen-Zvi B, Avni T, Gafter U, Gafter-Gvili A. Intravenous versus oral Iron supplementation for the treatment of Anemia in CKD: an updated systematic review and meta-analysis. Am J Kidney Dis. 2016;68(5):677–90.CrossRefPubMed Shepshelovich D, Rozen-Zvi B, Avni T, Gafter U, Gafter-Gvili A. Intravenous versus oral Iron supplementation for the treatment of Anemia in CKD: an updated systematic review and meta-analysis. Am J Kidney Dis. 2016;68(5):677–90.CrossRefPubMed
16.
go back to reference Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD, CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur Heart J. 2015;36(11):657–68.CrossRefPubMed Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD, CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur Heart J. 2015;36(11):657–68.CrossRefPubMed
17.
go back to reference Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr. 2001;131(2S-2):568S–79S. discussion 580SCrossRefPubMed Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr. 2001;131(2S-2):568S–79S. discussion 580SCrossRefPubMed
18.
go back to reference Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw D, De Jong PE. Prevend study group: microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249(6):519–26.CrossRefPubMed Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw D, De Jong PE. Prevend study group: microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249(6):519–26.CrossRefPubMed
19.
go back to reference Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, van Lente F, Greene T, Coresh J. CKD-EPI (chronic kidney disease epidemiology collaboration): a new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.CrossRefPubMedPubMedCentral Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, van Lente F, Greene T, Coresh J. CKD-EPI (chronic kidney disease epidemiology collaboration): a new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.CrossRefPubMedPubMedCentral
20.
go back to reference Anonymous Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5–37. Anonymous Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5–37.
21.
go back to reference Macdougall IC, Bock AH, Carrera F, Eckardt KU, Gaillard C, Van Wyck D, Roubert B, Nolen JG, Roger SD. FIND-CKD study investigators: FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant. 2014;29(11):2075–84.CrossRefPubMedPubMedCentral Macdougall IC, Bock AH, Carrera F, Eckardt KU, Gaillard C, Van Wyck D, Roubert B, Nolen JG, Roger SD. FIND-CKD study investigators: FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant. 2014;29(11):2075–84.CrossRefPubMedPubMedCentral
23.
go back to reference Qunibi WY, Martinez C, Smith M, Benjamin J, Mangione A, Roger SD. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant. 2011;26(5):1599–607.CrossRefPubMed Qunibi WY, Martinez C, Smith M, Benjamin J, Mangione A, Roger SD. A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. Nephrol Dial Transplant. 2011;26(5):1599–607.CrossRefPubMed
24.
go back to reference Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol. 1996;7(12):2654–7.PubMed Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol. 1996;7(12):2654–7.PubMed
25.
go back to reference Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H, Kleiner M, Luft FC. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis. 1995;26(2):292–9.CrossRefPubMed Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H, Kleiner M, Luft FC. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis. 1995;26(2):292–9.CrossRefPubMed
26.
go back to reference Kalantar-Zadeh K, Kalantar-Zadeh K, Lee GH. The fascinating but deceptive ferritin: to measure it or not to measure it in chronic kidney disease? Clin J Am Soc Nephrol. 2006;1(Suppl 1):S9–18.CrossRefPubMed Kalantar-Zadeh K, Kalantar-Zadeh K, Lee GH. The fascinating but deceptive ferritin: to measure it or not to measure it in chronic kidney disease? Clin J Am Soc Nephrol. 2006;1(Suppl 1):S9–18.CrossRefPubMed
27.
go back to reference Zandman-Goddard G, Shoenfeld Y. Ferritin in autoimmune diseases. Autoimmun Rev. 2007;6(7):457–63.CrossRefPubMed Zandman-Goddard G, Shoenfeld Y. Ferritin in autoimmune diseases. Autoimmun Rev. 2007;6(7):457–63.CrossRefPubMed
28.
go back to reference Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol. 2006;1(Suppl 1):S4–8.CrossRefPubMed Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol. 2006;1(Suppl 1):S4–8.CrossRefPubMed
Metadata
Title
Association of different iron deficiency cutoffs with adverse outcomes in chronic kidney disease
Authors
Michele F. Eisenga
Ilja M. Nolte
Peter van der Meer
Stephan J. L. Bakker
Carlo A. J. M. Gaillard
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2018
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-018-1021-3

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