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Introduction: Iron Management in Chronic Kidney Disease
VOL. 36, NO. 2
MARCH 2016
Introduction: Iron Management in Chronic Kidney Disease
A
fter the introduction of recombinant human erythropoietin (rHuEPO) in 1989, iron deficiency for the first time became a very frequent problem among patients on dialysis. Before that time, iron deficiency occurred, but was less common. In fact, iron overload was often a problem,1 primarily owing to frequent blood transfusions. It was not unusual to treat hemodialysis patients with iron chelation therapy. With the introduction of rHuEPO, patients’ underlying susceptibility to iron deficiency was exposed. During erythropoiesis, as hemoglobin levels increase, there is a great need for iron from storage tissues. This effect was observed in the early studies of rHuEPO, because patients’ serum ferritin concentrations decreased sharply during treatment (Fig. 1).2 By the mid-1990s nephrologists began to recognize the great prevalence of iron deficiency among hemodialysis patients. The first Kidney Disease Outcomes Quality Initiative, published in 1997, emphasized the need to test for iron status and treat with intravenous iron.3 Since that time, iron treatment in US hemodialysis patients has expanded substantially. The mean serum ferritin level in 2015 was more than 700 ng/mL,4 and intravenous iron treatment is almost universal. The current relevant Kidney Disease Improving Global Outcomes guideline statement is as follows, “for adult CKD [chronic kidney disease] patients on ESA [erythropoiesis stimulating agents] therapy who are not receiving iron supplementation, we suggest a trial of IV [intravenous] iron… if an increase in Hb [hemoglobin] concentration or a decrease in ESA dose is desired and TSAT [transferrin saturation] is o30% and ferritin is o500 ng/ml (500 mg/l).”5 There is an obvious disparity between the Kidney Disease Improving Global Outcomes guideline statement and actual clinical practice. In this issue of Seminars in Nephrology, we review iron management from a number of perspectives. We begin with a review of iron biology and issues concerning the diagnosis of iron status and treatment. Conflict of interest statement: Steven Fishbane has performed consulting and research for Keryx Pharmaceuticals and Rockwell, Inc. Financial support: none. 0270-9295/ - see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2016.02.009 Seminars in Nephrology, Vol 36, No 2, March 2016, pp 85–86
Figure 1. Five of the hemodialysis patients treated in phase 3 trials of epoetin alfa. During treatment, as the hemoglobin level increased there was a dramatic decrease in serum ferritin level. This is the usual effect of erythropoiesis as iron is transferred out of storage tissues and into the developing erythron.
Special attention is given to the major advances in the understanding of iron homeostasis that have occurred over the past decade. Next, the subject of current knowledge on iron safety is reviewed in great depth. This leads to a review of balancing the benefits and safety of iron treatment, and why it currently is difficult to develop an approach to informed iron treatment. The issue concludes with a focused look at newer iron treatment agents that moves beyond intravenous iron agents.
REFERENCES 1. Ali M, Fayemi AO, Rigolosi R, Frascino J, Marsden T, Malcolm D. Hemosiderosis in hemodialysis patients. An autopsy study of 50 cases. JAMA. 1980;244:343-5.
85
86 2. Eschbach JW. The anemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney Int. 1989;35:134-48. 3. NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. National Kidney FoundationDialysis Outcomes Quality Initiative. Am J Kidney Dis. 1997;30 (Suppl 3):S192-240. 4. [cited 2015 October 2]. Available from: http://www.dopps.org/ DPM/DPMSlideBrowser.aspx?type=Topic&id=1.
S. Fishbane 5. [cited 2015 October 15]. Available from: http://www.kdigo.org/ clinical_practice_guidelines/pdf/KDIGO-Anemia%20GL.pdf.
Steven Fishbane, MD Guest Editor Department of Medicine, Division of Nephrology Hofstra North Shore-LIJ School of Medicine Great Neck, NY
MARCH 2016
Introduction: Iron Management in Chronic Kidney Disease
A
fter the introduction of recombinant human erythropoietin (rHuEPO) in 1989, iron deficiency for the first time became a very frequent problem among patients on dialysis. Before that time, iron deficiency occurred, but was less common. In fact, iron overload was often a problem,1 primarily owing to frequent blood transfusions. It was not unusual to treat hemodialysis patients with iron chelation therapy. With the introduction of rHuEPO, patients’ underlying susceptibility to iron deficiency was exposed. During erythropoiesis, as hemoglobin levels increase, there is a great need for iron from storage tissues. This effect was observed in the early studies of rHuEPO, because patients’ serum ferritin concentrations decreased sharply during treatment (Fig. 1).2 By the mid-1990s nephrologists began to recognize the great prevalence of iron deficiency among hemodialysis patients. The first Kidney Disease Outcomes Quality Initiative, published in 1997, emphasized the need to test for iron status and treat with intravenous iron.3 Since that time, iron treatment in US hemodialysis patients has expanded substantially. The mean serum ferritin level in 2015 was more than 700 ng/mL,4 and intravenous iron treatment is almost universal. The current relevant Kidney Disease Improving Global Outcomes guideline statement is as follows, “for adult CKD [chronic kidney disease] patients on ESA [erythropoiesis stimulating agents] therapy who are not receiving iron supplementation, we suggest a trial of IV [intravenous] iron… if an increase in Hb [hemoglobin] concentration or a decrease in ESA dose is desired and TSAT [transferrin saturation] is o30% and ferritin is o500 ng/ml (500 mg/l).”5 There is an obvious disparity between the Kidney Disease Improving Global Outcomes guideline statement and actual clinical practice. In this issue of Seminars in Nephrology, we review iron management from a number of perspectives. We begin with a review of iron biology and issues concerning the diagnosis of iron status and treatment. Conflict of interest statement: Steven Fishbane has performed consulting and research for Keryx Pharmaceuticals and Rockwell, Inc. Financial support: none. 0270-9295/ - see front matter & 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2016.02.009 Seminars in Nephrology, Vol 36, No 2, March 2016, pp 85–86
Figure 1. Five of the hemodialysis patients treated in phase 3 trials of epoetin alfa. During treatment, as the hemoglobin level increased there was a dramatic decrease in serum ferritin level. This is the usual effect of erythropoiesis as iron is transferred out of storage tissues and into the developing erythron.
Special attention is given to the major advances in the understanding of iron homeostasis that have occurred over the past decade. Next, the subject of current knowledge on iron safety is reviewed in great depth. This leads to a review of balancing the benefits and safety of iron treatment, and why it currently is difficult to develop an approach to informed iron treatment. The issue concludes with a focused look at newer iron treatment agents that moves beyond intravenous iron agents.
REFERENCES 1. Ali M, Fayemi AO, Rigolosi R, Frascino J, Marsden T, Malcolm D. Hemosiderosis in hemodialysis patients. An autopsy study of 50 cases. JAMA. 1980;244:343-5.
85
86 2. Eschbach JW. The anemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney Int. 1989;35:134-48. 3. NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. National Kidney FoundationDialysis Outcomes Quality Initiative. Am J Kidney Dis. 1997;30 (Suppl 3):S192-240. 4. [cited 2015 October 2]. Available from: http://www.dopps.org/ DPM/DPMSlideBrowser.aspx?type=Topic&id=1.
S. Fishbane 5. [cited 2015 October 15]. Available from: http://www.kdigo.org/ clinical_practice_guidelines/pdf/KDIGO-Anemia%20GL.pdf.
Steven Fishbane, MD Guest Editor Department of Medicine, Division of Nephrology Hofstra North Shore-LIJ School of Medicine Great Neck, NY